Anthelmintic depsipeptide compounds

ABSTRACT

The present invention provides cyclic depsipeptide compounds of formula (I) wherein the stereochemical configuration of at least one carbon atom bearing the groups Cy 1 , Cy 2 , R 1 , R 2 , R 3 , R 4 , R a  and R b  is inverted compared with the naturally occurring cyclic depsipeptide PF1022A. The invention also provides compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.

FIELD OF THE INVENTION

The present invention is directed to new anthelmintic depsipeptidescompounds with excellent activity against endoparasites andectoparasites. The invention is also directed to compositions comprisingthe compounds and methods and uses of the compounds for eradicating,controlling, and preventing a parasite infestation and/or infection inanimals. The compounds of the invention may be administered to animals,particularly mammals, fish and birds, to prevent or treat parasiticinfections.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 62/423,182 filed Nov. 16, 2016, which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Animals, such as mammals and birds, are often susceptible to parasiteinfestations. These parasites may be ectoparasites, such as fleas andticks. Animals and humans also suffer from endoparasitic infectionsincluding, for example, helminthiasis which is most frequently caused bya group of parasitic worms described as nematodes or roundworms. Theseparasites cause severe economic losses in pigs, sheep, horses, andcattle as well as affecting companion animals (e.g. cats and dogs) andpoultry. Other parasites include those which occur in thegastrointestinal tract of animals and humans include Ancylostoma,Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara,Toxascaris, Trichuris, Enterobius and parasites which are found in theblood or other tissues and organs such as filarial worms and the extraintestinal stages of Strongyloides, Toxocara and Trichinella.

One type of endoparasite which seriously harms mammals is Dirofilariaimmitis, also known as Heartworm. Other filarial endoparasites includeDirofilaria repens and Dirofilaria honkongensis, which can also infecthumans. The most common hosts are dogs and cats but other mammals suchas ferrets and raccoons may also be infected. Heartworms go throughseveral life stages before they become adults infecting the pulmonaryartery of the host mammal. The worms require the mosquito as anintermediate host to complete their life cycle. The period between theinitial infection when the dog is bitten by a mosquito and thematuration of the worms into adults living in the heart and pulmonaryarteries is six to seven months in dogs and is known as the “prepatentperiod”. L3 larvae migrate during blood feeding of the mosquito to thetip of the mosquito's mouth parts (labium), leave the mosquito and aredeposited on the skin of the dog where they then migrate through thebite wound into the host. Most L3 larvae molt to fourth-stage larvae(L4s) in canine subcutaneous tissues within 1-3 days after infection.Then, they migrate to the muscles of the chest and abdomen, and 45 to 60days after infection, molt to the fifth stage (L5, immature adult).Between 75 and 120 days after infection, these immature heartworms thenenter the bloodstream and are carried through the heart to reside in thepulmonary artery. Around seven months after infection, Dirofilariaimmitis adults reach maturity and sexually reproduce in the pulmonaryarteries and right ventricle. Adult males are around 15 cm in length,and females are around 25 cm in length and their normal life span asadults is calculated to be about 5 years.

Heartworm infection is a severe and life-threatening disease. Canineheartworm infection is preventable and prophylaxis treatment is apriority in heartworm endemic areas. Treatment of mature heartworminfection with an adulticide (e.g. melarsomine dihydrochloride) iscostly and can cause serious adverse side effects, thus prevention bymonthly administration of drugs that interrupt larvae development iswidely used. The goal of marketed heartworm preventive therapies in dogsis to prevent the development of the parasite to adult heartworms byinterrupting the Dirofilaria immitis life cycle post-infection.

The macrocyclic lactones (MLs, e.g. ivermectin, eprinomectin, milbemycinoxime, moxidectin, and selamectin) are the most commonly usedchemoprophylaxis agents and are administered at monthly or six-monthintervals. These drugs have been effective against Dirofilaria immitisinfective third-stage larvae (L3) deposited by the mosquito as well asmaturing fourth-stage larvae (L4). When administered monthly, MLs killL3 and L4 larvae acquired within the previous 30 days, and thus preventdisease caused by adult worms. MLs can also be used monthly in infecteddogs to suppress reproduction in adult worms and remove microfilariae,thereby reducing transmission and gradually causing the attrition ofadult worms (Vet. Parasitol. 2005 Oct. 24 133(2-3) 197-206).

In recent years, an increased number of lack of efficacy (LOE) caseshave been reported, in which dogs develop mature heartworm infectionsdespite receiving monthly prophylactic doses of macrocyclic lactonesdrugs. For example, Atkins et al., (Vet. Parasitol. 206 (2014) 106-113)recently reported that an increasing number of cases of dogs that testedheartworm antigen positive while receiving heartworm preventivemedication which suggests that some populations of Dirofilaria immitishave developed selectional resistance to heartworm preventives (AmericanHeartworm Society, 2010. Heartworm Preventive Resistance. Is itPossible, vol. 37. Bulletin of the American Heartworm Society, pp. 5.).Thus, there is an ongoing need to develop new anthelmintic agents withimproved activity against Dirofilaria immitis and other endoparasites.

Various parasiticides exist in the art for treating endoparasitesinfections in animals. In addition to the macrocyclic lactones, cyclicdepsipeptides with antiparasitic activity are known. PF1022A, a24-membered cyclooctadepsipeptide isolated from the fungus Myceliasterilia by Sasaki et al. (see J. Antibiotics 45: 692-697 (1992)), hasbeen found to exhibit broad anthelmintic activity against a variety ofendoparasites in vivo with low toxicity. The structure of PF1022A isshown below with the absolute stereochemical configuration of the chiralcarbon atoms indicated:

These compounds are described, for example, in U.S. Pat. Nos. 5,514,773;5,747,448; 5,646,244; 5,874,530; among others, which are incorporatedherein by reference. Emodepside is a semi synthetic analog of PF1022Acontaining a morpholine group at the para position of the aryl ring inthe phenyl lactate groups. Emodepside is a potent anthelmintic used incombination with praziquantel in the product Profender® for thetreatment of parasitic worms in cats and dogs. However, theanti-parasitic activity of PF1022A and emodepside is not satisfactoryfor the treatment of certain parasites, especially for the control ofDirofilaria immitis in mammals to prevent the establishment of heartwormdisease. Thus, there is a need in the art for more effectiveantiparasitic agents for treatment and protection of animals, e.g.mammals, fish and birds against parasites, in particular internalparasites including nematodes and filarial worms such as heartworm.

It is expressly noted that citation or identification of any document inthis application is not an admission that such document is available asprior art to the present invention. Any foregoing applications, and alldocuments cited therein or during their prosecution (“application citeddocuments”) and all documents cited or referenced in the applicationcited documents, and all documents cited or referenced herein (“hereincited documents”), and all documents cited or referenced in herein citeddocuments, together with any manufacturer's instructions, descriptions,product specifications, and product sheets for any products mentionedherein or in any document incorporated by reference herein, are herebyincorporated herein by reference, and may be employed in the practice ofthe invention.

SUMMARY OF THE INVENTION

The invention provides novel and inventive cyclic depsipeptide compoundswith superior anthelmintic activity. The compounds of the invention are24-membered cyclic depsipeptides that are related to the naturallyoccurring compound PF1022A wherein the stereochemical configuration ofat least one of the chiral centers is inverted in comparison with thecorresponding chiral center of naturally-occurring PF1022A. In addition,in the compounds of the invention at least one of the phenyl rings ofthe phenyl lactate moieties and/or at least of the one of the2-methylpropyl groups of the naturally occurring N-methyl leucinemoieties of PF1022A are substituted with certain substituents. Theinvention also provides compositions comprising the novel depsipeptidecompounds, methods and uses comprising the depsipeptide compounds forthe treatment and prevention of parasitic infection and/or infestationof animals using the compounds.

In one embodiment, the present invention provides cyclic depsipeptidecompounds of formula (I) shown below:

or a veterinarily acceptable salt thereof, wherein Cy¹, Cy², R¹, R², R³,R⁴, R^(a), R^(b), R′, R″, R′″ and R″″ are as defined below, and whereinthe stereochemical configuration of at least one of the carbon atomsbearing the groups —CH₂—Cy¹, —CH₂—Cy², R¹, R², R³, R⁴, R^(a) and R^(b)has a stereochemical configuration that is inverted compared with thestereochemical configuration for the corresponding carbon atom in thenatural product PF1022A. For example, in PF1022A the carbon atomsbearing the —CH₂Ph groups of the phenyl lactate moities have the(R)-configuration. In the compounds of formula (I) of the inventionwherein the carbon atoms bearing the —CH₂Cy¹ and/or —CH₂Cy² groups havethe inverted stereochemical configuration, they would have the(S)-configuration.

The invention also provides veterinary compositions comprising theinventive compounds, or salts thereof, in combination with apharmaceutically acceptable carrier or diluent.

In another embodiment, the invention provides a salt form of the noveldepsipeptide compounds of the invention.

The inventive compounds and compositions comprising the compounds arehighly effective for the treatment and prophylaxis of internal parasitesin mammals, fish and birds, and in particular, cats, dogs, horses,chickens, pigs, sheep and cattle with the aim of ridding these hosts ofall the endoparasites commonly encountered by mammals, fish and birds.

In one embodiment, the compounds and compositions of the invention arehighly effective against endoparasites, such as filariae (e.g.heartworm), hookworms, whipworms and roundworms of the digestive tractof animals and humans. In certain embodiments, the compounds andcompositions of the invention are effective against Dirofilaria immitis(heartworm) isolates that are less sensitive to treatment withmacrocyclic lactones. In another embodiment, the novel and inventivedepsipeptides of the invention are effective for treating and preventinginfections of animals with nematodes that are less sensitive totreatment with commercially available or known macrocyclic lactoneactive agents.

In certain embodiments, the invention provides compositions comprising acombination of a novel depsipeptide of the invention in combination withat least a second active agent, which broadens the scope of protectionafforded to animals against endoparasites and possibly alsoectoparasites.

The present invention is also directed to methods for the treatment andprevention of a parasitic infection or infestation in an animalcomprising administering at least one of the compounds of formula (I) ofthe invention to the animal. Also included in the present invention areuses of the compounds for the treatment and/or prevention of a parasiticinfection and/or infestation in animals and the use of the compounds inthe preparation of a medicament for the treatment and/or prevention of aparasitic infection and/or infestation in an animal.

It is an object of the invention to not encompass within the inventionany previously known product, process of making the product, or methodof using the product such that the Applicants reserve the right to thisinvention and hereby disclose a disclaimer of any previously knownproduct, process, or method.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. Patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. Patent law;e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are obvious from, andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

The present invention provides novel and inventive cyclic depsipeptidecompounds of formula (I) having parasiticidal activity againstendoparasites, and also against ectoparasites in certain embodiments, orveterinarily salts thereof, and compositions comprising the compounds orsalts, for the treatment or prevention of parasitic infections and/orinfestations in an animal. Also provided are methods for the treatmentor prevention of parasitic infestations and/or infection in animals,comprising administering an effective amount of the depsipeptidecompound of the invention, or a salt thereof, to the animal.

The novel and inventive cyclic depsipeptide of formula (I) describedherein and their pharmaceutically or veterinarily acceptable salts areparticularly effective for controlling endoparasites. Endoparasitesinclude, but are not limited to, nematodes (such as roundworms,hookworms, and whipworms) and filarial worms such as Dirofilaria immitis(heartworm). In certain embodiments, the novel cyclic depsipeptides ofthe invention have been found to have significantly higher efficacyagainst endoparasites compared with known cyclic depsipeptides includingPF1022A and emodepside. Furthermore, it has been discovered that thenovel cyclic depsipeptides of the invention are significantly moreresistant to metabolic modification in the body of animals so that theymaintain at a higher concentration in the host animal's body and ahigher level of activity against internal parasites for a longerduration of time.

In one embodiment, the cyclic depsipeptides of the invention have beenfound to be highly effective against filarial worms such as Dirofilariaimmitis (microfilarial and larval stages), including isolates of theparasite that are resistant to macrocyclic lactones. In otherembodiments, the compounds of the invention are effective againstendoparasites that are not effectively controlled by the known cyclicdepsipeptides such as PF1022A and emodepside.

In another embodiment, certain cyclic depsipeptides of the inventionhave been found to have activity against ectoparasites such as fleas andticks. Thus, in certain embodiments the cyclic depsipeptides may haveendectocidal activity against both internal and external parasites.

The invention includes at least the following features:

-   -   (a) In one embodiment, the invention provides novel cyclic        depsipeptide compounds of formula (I), or pharmaceutically or        veterinarily acceptable salts thereof, which are active against        endoparasites and in some cases also active against        ectoparasites;

(b) veterinary compositions comprising a parasiticidally effectiveamount of the cyclic depsipeptide compounds of formula (I), or apharmaceutically or veterinarily acceptable salt thereof, in combinationwith a pharmaceutically or veterinarily acceptable carrier or diluent;

(c) veterinary compositions comprising a parasiticidally effectiveamount of the cyclic depsipeptide compounds of the invention, orpharmaceutically or veterinarily acceptable salts thereof, incombination with one more other active agents and a pharmaceutically orveterinarily acceptable carrier or diluent;

(d) methods for treating a parasitic infestation and/or infection in oron an animal are provided comprising administering a parasiticidallyeffective amount of a cyclic depsipeptide compound of formula (I), or apharmaceutically or veterinarily acceptable salts thereof, optionallywith one or more additional active agents, to the animal in needthereof;

(e) methods for the prevention of a parasitic infestation and/orinfection of an animal, which comprise administering a parasiticidallyeffective amount of a cyclic depsipeptide compound of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, optionallywith one or more additional active agents, to the animal in needthereof;

(f) use of the cyclic depsipeptide compounds of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, for thetreatment or prevention of a parasitic infection and/or a parasiticinfestation in an animal;

(g) uses of the cyclic depsipeptide compounds of formula (I), orpharmaceutically or veterinarily acceptable salts thereof, in themanufacture of a veterinary medicament for the treatment or preventionof a parasitic infection and/or infestation in an animal; and

(h) processes for the preparation of the compounds of formula (I).

Definitions

Terms used herein will have their customary meanings in the art unlessspecified. The organic moieties mentioned in the definitions of thevariables of the cyclic depsipeptide formula (I) are like the termhalogen—i.e., collective terms for individual listings of the individualgroup members—fluoro, chloro, bromo and iodo with respect to halogen.The prefix C_(n)-C_(m) indicates in each case the possible number ofcarbon atoms in the group.

The term “alkyl” refers to saturated straight, branched, primary,secondary or tertiary hydrocarbons, including those having 1 to 12atoms. In some embodiments, alkyl groups will include C₁-C₁₀, C₁-C₈,C₁-C₆, C₁-C₄ or C₁-C₃ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups, may be referred to as “cycloalkyl” and includethose with 3 to 10 carbon atoms having single or multiple fused rings.Non-limiting examples of cycloalkyl groups include adamantyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like.

Carbocyclic groups are cyclic groups composed exclusively of carbon. Thecarbocyclic groups include both aromatic rings such as phenyl andnon-aromatic rings such cyclohexyl and include those with 3 to 14 carbonatoms having single or multiple fused rings.

The alkyl and cycloalkyl and carbocyclic groups described herein can beunsubstituted or substituted with one or more moieties selected from thegroup consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl,acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy,aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate,sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl,phosphoryl, phosphine, thioester, thioether, acid halide, anhydride,oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, orany other viable functional group that does not inhibit the biologicalactivity of the compounds of the invention, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene and Wuts, Protective Groups in OrganicSynthesis, John Wiley and Sons, Third Edition, 1999, hereby incorporatedby reference.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In some embodiments,alkenyl groups may include C₂-C₁₂ alkenyl groups. In other embodiments,alkenyl includes C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl groups. In oneembodiment of alkenyl, the number of double bonds is 1-3; in anotherembodiment of alkenyl, the number of double bonds is one. Other rangesof carbon-carbon double bonds and carbon numbers are also contemplateddepending on the location of the alkenyl moiety on the molecule.“C₂-C₁₀-alkenyl” groups may include more than one double bond in thechain. Examples include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl,2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Cycloalkenyl” refers to monovalent cyclic alkenyl groups of from 4 to10 carbon atoms, preferably 5 to 8 carbon atoms, having single ormultiple fused rings which fused rings may or may not be cycloalkenylprovided that the point of attachment is to a cycloalkenyl ring atom.Examples of cycloalkenyl groups include, by way of example,cyclopenten-4-yl, cyclooctene-5-yl and the like. Alkenyl andcycloalkenyl groups may be unsubstituted or substituted with one or moresubstituents as described for alkyl above.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. In one embodiment of alkynyl,the number of triple bonds is 1-3; in another embodiment of alkynyl, thenumber of triple bonds is one. In some embodiments, alkynyl groupsinclude from 2 to 12 carbon atoms. In other embodiments, alkynyl groupsmay include C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups. Other rangesof carbon-carbon triple bonds and carbon numbers are also contemplateddepending on the location of the alkenyl moiety on the molecule. Forexample, the term “C₂-C₁₀-alkynyl” as used herein refers to astraight-chain or branched unsaturated hydrocarbon group having 2 to 10carbon atoms and containing at least one triple bond, such as ethynyl,prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl,n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl,n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl,n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl,n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl,n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl,n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl,3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl,3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-ylor 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl,2-fluoro-2-methylpropyl and the like.

The term “fluoroalkyl” as used herein refers to an alkyl in which one ormore of the hydrogen atoms is replaced with fluorine atoms, for exampledifluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl,2-fluoro-2-methylpropyl or pentafluoroethyl.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, OCH₂—C₂H₅, OCH(CH₃)₂, n-butoxy,OCH(CH₃)—C₂H₅, OCH₂—CH(CH₃)₂, OC(CH₃)₃, n-pentoxy, 1-methylbutoxy,2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple fused rings. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, and naphthyl. In someembodiments aryl includes tetrahydronaphthyl, phenylcyclopropyl andindanyl. Aryl groups may be unsubstituted or substituted by one or moremoieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy,alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy,cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy,alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio,alkylsulfinyl, alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, —SF₅, alkylamino,alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)-amino,di(alkynyl)amino, or trialkylsilyl.

The term “aralkyl” refers to an aryl group that is bonded to the parentcompound through a diradical alkylene bridge, (—CH₂-)_(n), where n is1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. In one embodiment, the termheteroaryl includes 5-membered and 6-membered heteroaryl groups. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple fused rings provided that the point of attachment is through aheteroaryl ring atom. Examples of heteroaryls include pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl,thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,isothiazolyl, pyrazolyl benzofuranyl, benzothiophenyl, imidazopyridyl,imidazopyrimidyl, or pyrrolopyrimidyl. Heteroaryl rings may beunsubstituted or substituted by one or more moieties as described foraryl above.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refers to fullysaturated or unsaturated, cyclic groups, for example, 3 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring systems, which have one or more oxygen, sulfur or nitrogenheteroatoms in ring, preferably numbering 1 to 4 or 1 to 3 heteroatoms.The nitrogen and sulfur heteroatoms may optionally be oxidized and thenitrogen heteroatoms may optionally be quaternized. The heterocyclicgroup may be attached at any heteroatom or carbon atom of the ring orring system and may be unsubstituted or substituted by one or moremoieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolyl, pyrazolyl,oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl,oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl,thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl,tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and the like.

The term “alkylthio” refers to alkyl-S—, where “alkyl” is as definedabove. In some embodiments, the alkyl component of the alkylthio groupwill include C₁-C₁₀, C₁-C₈, C₁-C₆ C₁-C₄ or C₁-C₃ alkyl groups. Forexample, C₁-C₄-alkylthio include, but are not limited to, methylthio,ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio,2-methylpropylthio or 1,1-dimethylethylthio.

Similarly, the terms “haloalkylthio,” “cycloalkylthio,”“halocycloalkylthio” refer to the groups —S-haloalkyl, —S-cycloalkyl,and —S-halocycloalkyl, respectively, where the terms “haloalkyl,”“cycloalkyl,” and “halocycloalkyl” are as defined above.

The term “alkylsulfinyl” refers to the group alkyl-S(═O)—, where “alkyl”is as defined above. In some embodiments, the alkyl component inalkylsulfinyl groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₄ orC₁-C₃ alkyl groups. Examples include, but are not limited to, —SO—CH₃,—SO—C₂H₅, n-propylsulfinyl, 1-methylethyl sulfinyl, n-butylsulfinyl,1-methylpropylsulfinyl, 2-methylpropylsulfinyl, 1,1-dimethylethylsulfinyl, n-pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutyl sulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

Similarly, the terms “alkenylsulfinyl,” “alkynylsulfinyl,”“haloalkylsulfinyl,” “haloalkenylsulfinyl,” and “haloalkynylsulfinyl”refer to the groups alkenyl-S(═O)—, alkynyl-S(═O)—, andhaloalkyl-S(═O)—, haloalkenyl-S(═O)—, and haloalkynyl-S(═O)—, where theterms “alkenyl,” “alkynyl,” “haloalkyl,” “haloalkenyl,” and“haloalkynyl” are as defined above.

The term “alkylsulfonyl” refers to the group alkyl-S(═O)₂—, where theterm “alkyl” is as defined above. In some embodiments, the alkylcomponent in alkylsulfonyl groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈,C₁-C₆ or C₁-C₄ alkyl groups. Examples include, but are not limited to,—SO₂—CH₃, —SO₂—C₂H₅, n-propylsulfonyl, —SO₂—CH(CH₃)₂, n-butylsulfonyl,1-methylpropylsulfonyl, 2-methylpropylsulfonyl, —SO₂—C(CH₃)₃,n-pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl,3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl,1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl,1-ethylpropylsulfonyl, n-hexylsulfonyl, 1-methylpentylsulfonyl,2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl,1,1-dimethylbutyl sulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropyl sulfonyl,1-ethyl-1-methylpropyl sulfonyl or 1-ethyl-2-methylpropylsulfonyl andthe like.

The terms “alkenylfulfonyl,” “alkynylsulfonyl,” “haloalkylsulfonyl,”“haloalkenylsulfonyl,” and “haloalkynylsulfonyl” refer to the groupsalkenyl-S(═O)₂—, alkynyl-S(═O)₂—, and haloalkyl-S(═O)₂—,haloalkenyl-S(═O)₂—, and haloalkynyl-S(═O)₂—, where the terms “alkenyl,”“alkynyl,” “haloalkyl,” “haloalkenyl,” and “haloalkynyl” are as definedabove.

The terms “alkylamino,” “dialkylamino,” “alkenylamino,” “alkynylamino,”“di(alkenyl)amino,” and “di(alkynyl)amino” refer to the groups—NH(alkyl), —N(alkyl)₂, —NH(alkenyl), —NH(alkynyl), —N(alkenyl)₂ and—N(alkynyl)₂, where the terms “alkyl,” “alkenyl,” and “alkynyl” are asdefined above. In some embodiments, the alkyl component in alkylamino ordialkylamino groups will include C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆ or C₁-C₄alkyl groups.

Compounds of the Invention:

The compounds of the invention are 24-membered cyclic depsipeptidecompounds which have potent activity against endoparasites such asnematodes and filarial worms (microfilarial and larval stages) and alsoin some cases against ectoparasites such as fleas and ticks. In oneembodiment the invention provides cyclic depsipeptide compounds offormula:

or a veterinarily acceptable salt thereof, wherein:

Cy¹ and Cy² are independently aryl, carbocyclic, heteroaryl orheterocyclic optionally substituted with one or more substituentsselected from the group consisting of halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino,dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O—heterocyclyl or —S-heterocyclyl, wherein each cycloalkyl, heteroalkyl,aryl or heteroaryl is optionally further substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—,

R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and—NO₂; R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl; and

(a) R¹ is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and

R², R³ and R⁴ are each independently C₁-C₈ alkyl; or

(b) R² is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and

R¹, R³ and R⁴ are each independently C₁-C₈ alkyl; or

(c) R³ is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and

R¹, R² and R⁴ are each independently C₁-C₈ alkyl; or

(d) R⁴ is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and

R¹, R² and R³ are each independently C₁-C₈ alkyl; or

(e) R¹ and R² are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R³ and R⁴ are each independently C₁-C₈ alkyl; or

(f) R¹ and R³ are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R² and R⁴ are each independently C₁-C₈ alkyl; or

(g) R¹ and R⁴ are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R² and R³ are each independently C₁-C₈ alkyl; or

(h) R² and R⁴ are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R¹ and R³ are each independently C₁-C₈ alkyl; or

(i) R² and R³ are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R¹ and R⁴ are each independently C₁-C₈ alkyl; or

(j) R³ and R⁴ are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R¹ and R² are each independently C₁-C₈ alkyl; or

(k) R¹, R² and R³ are each independently C₁-C₈ alkyl substituted by oneor more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R⁴ is C₁-C₈ alkyl; or

(1) R², R³ and R⁴ are each independently C₁-C₈ alkyl substituted by oneor more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R¹ is C₁-C₈ alkyl; or

(m) R¹, R³ and R⁴ are each independently C₁-C₈ alkyl substituted by oneor more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

R² is C₁-C₈ alkyl; or

(n) R¹, R² and R⁴ are each independently C₁-C₈ alkyl substituted by oneor more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino andalkylamino, dialkylamino; and

R³ is C₁-C₈ alkyl; or

(o) R¹, R², R³ and R⁴ are each independently C₁-C₈ alkyl substituted byone or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and

wherein the stereochemical configuration of the carbon atoms bearing thegroups —CH₂—Cy¹, —CH₂—Cy², R¹, R², R³, R⁴, R^(a) and R^(b) is selectedfrom Tables 1 to 5 below with reference to stereochemical configurationof the corresponding carbon atoms in naturally-occurring PF1022A.

TABLE 1 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 invertednatural natural natural natural natural natural natural 2 naturalinverted natural natural natural natural natural natural 3 invertedinverted natural natural natural natural natural natural 4 naturalnatural natural natural natural natural natural natural 5 invertednatural natural natural natural natural inverted natural 6 naturalinverted natural natural natural natural inverted natural 7 invertedinverted natural natural natural natural inverted natural 8 naturalnatural natural natural natural natural inverted natural 9 invertednatural natural natural natural natural natural inverted 10 naturalinverted natural natural natural natural natural inverted 11 invertedinverted natural natural natural natural natural inverted 12 naturalnatural natural natural natural natural natural inverted 13 invertednatural natural natural natural natural inverted inverted 14 naturalinverted natural natural natural natural inverted inverted 15 invertedinverted natural natural natural natural inverted inverted 16 naturalnatural natural natural natural natural inverted inverted

TABLE 2 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 naturalnatural inverted natural natural natural natural natural 2 naturalnatural natural inverted natural natural natural natural 3 naturalnatural natural natural inverted natural natural natural 4 naturalnatural natural natural natural inverted natural natural 5 naturalnatural inverted natural inverted natural natural natural 6 naturalnatural natural inverted natural inverted natural natural 7 naturalnatural inverted inverted natural natural natural natural 8 naturalnatural natural natural inverted inverted natural natural 9 naturalnatural natural inverted inverted natural natural natural 10 naturalnatural inverted natural natural inverted natural natural 11 naturalnatural inverted inverted inverted natural natural natural 12 naturalnatural natural inverted inverted inverted natural natural 13 naturalnatural inverted natural inverted inverted natural natural 14 naturalnatural inverted inverted natural inverted natural natural 15 naturalnatural inverted inverted inverted inverted natural natural 16 naturalnatural inverted natural natural natural inverted natural 17 naturalnatural natural inverted natural natural inverted natural 18 naturalnatural natural natural inverted natural inverted natural 19 naturalnatural natural natural natural inverted inverted natural 20 naturalnatural inverted natural inverted natural inverted natural 21 naturalnatural natural inverted natural inverted inverted natural 22 naturalnatural inverted inverted natural natural inverted natural 23 naturalnatural natural inverted inverted natural inverted natural 24 naturalnatural natural natural inverted inverted inverted natural 25 naturalnatural inverted natural natural inverted inverted natural 26 naturalnatural inverted inverted inverted natural inverted natural 27 naturalnatural natural inverted inverted inverted inverted natural 28 naturalnatural inverted natural inverted inverted inverted natural 29 naturalnatural inverted inverted natural inverted inverted natural 30 naturalnatural inverted inverted inverted inverted inverted natural 31 naturalnatural inverted natural natural natural natural inverted 32 naturalnatural natural inverted natural natural natural inverted 33 naturalnatural natural natural inverted natural natural inverted 34 naturalnatural natural natural natural inverted natural inverted 35 naturalnatural inverted natural inverted natural natural inverted 36 naturalnatural natural inverted natural inverted natural inverted 37 naturalnatural inverted inverted natural natural natural inverted 38 naturalnatural natural inverted inverted natural natural inverted 39 naturalnatural natural natural inverted inverted natural inverted 40 naturalnatural inverted natural natural inverted natural inverted 41 naturalnatural inverted inverted inverted natural natural inverted 42 naturalnatural natural inverted inverted inverted natural inverted 43 naturalnatural inverted natural inverted inverted natural inverted 44 naturalnatural inverted inverted natural inverted natural inverted 45 naturalnatural inverted inverted inverted inverted natural inverted 46 naturalnatural inverted natural natural natural inverted inverted 47 naturalnatural natural inverted natural natural inverted inverted 48 naturalnatural natural natural inverted natural inverted inverted 49 naturalnatural natural natural natural inverted inverted inverted 50 naturalnatural inverted natural inverted natural inverted inverted 51 naturalnatural natural inverted natural inverted inverted inverted 52 naturalnatural inverted inverted natural natural inverted inverted 53 naturalnatural natural inverted inverted natural inverted inverted 54 naturalnatural natural natural inverted inverted inverted inverted 55 naturalnatural inverted natural natural inverted inverted inverted 56 naturalnatural inverted inverted inverted natural inverted inverted 57 naturalnatural natural inverted inverted inverted inverted inverted 58 naturalnatural inverted natural inverted inverted inverted inverted 59 naturalnatural inverted inverted natural inverted inverted inverted 60 naturalnatural inverted inverted inverted inverted inverted inverted

TABLE 3 Entry —CH₂Cy¹ —CH₂Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 inverted naturalinverted natural natural natural natural natural 2 inverted naturalnatural inverted natural natural natural natural 3 inverted naturalnatural natural inverted natural natural natural 4 inverted naturalnatural natural natural inverted natural natural 5 inverted naturalinverted natural inverted natural natural natural 6 inverted naturalnatural inverted natural inverted natural natural 7 inverted naturalinverted inverted natural natural natural natural 8 inverted naturalnatural inverted inverted natural natural natural 9 inverted naturalnatural natural inverted inverted natural natural 10 inverted naturalinverted natural natural inverted natural natural 11 inverted naturalinverted inverted inverted natural natural natural 12 inverted naturalnatural inverted inverted inverted natural natural 13 inverted naturalinverted natural inverted inverted natural natural 14 inverted naturalinverted inverted natural inverted natural natural 15 inverted naturalinverted inverted inverted inverted natural natural 16 inverted naturalinverted natural natural natural inverted natural 17 inverted naturalnatural inverted natural natural inverted natural 18 inverted naturalnatural natural inverted natural inverted natural 19 inverted naturalnatural natural natural inverted inverted natural 20 inverted naturalinverted natural inverted natural inverted natural 21 inverted naturalnatural inverted natural inverted inverted natural 22 inverted naturalinverted inverted natural natural inverted natural 23 inverted naturalnatural inverted inverted natural inverted natural 24 inverted naturalnatural natural inverted inverted inverted natural 25 inverted naturalinverted natural natural inverted inverted natural 26 inverted naturalinverted inverted inverted natural inverted natural 27 inverted naturalnatural inverted inverted inverted inverted natural 28 inverted naturalinverted natural inverted inverted inverted natural 29 inverted naturalinverted inverted natural inverted inverted natural 30 inverted naturalinverted inverted inverted inverted inverted natural 31 inverted naturalinverted natural natural natural natural inverted 32 inverted naturalnatural inverted natural natural natural inverted 33 inverted naturalnatural natural inverted natural natural inverted 34 inverted naturalnatural natural natural inverted natural inverted 35 inverted naturalinverted natural inverted natural natural inverted 36 inverted naturalnatural inverted natural inverted natural inverted 37 inverted naturalinverted inverted natural natural natural inverted 38 inverted naturalnatural inverted inverted natural natural inverted 39 inverted naturalnatural natural inverted inverted natural inverted 40 inverted naturalinverted natural natural inverted natural inverted 41 inverted naturalinverted inverted inverted natural natural inverted 42 inverted naturalnatural inverted inverted inverted natural inverted 43 inverted naturalinverted natural inverted inverted natural inverted 44 inverted naturalinverted inverted natural inverted natural inverted 45 inverted naturalinverted inverted inverted inverted natural inverted 46 inverted naturalinverted natural natural natural inverted inverted 47 inverted naturalnatural inverted natural natural inverted inverted 48 inverted naturalnatural natural inverted natural inverted inverted 49 inverted naturalnatural natural natural inverted inverted inverted 50 inverted naturalinverted natural inverted natural inverted inverted 51 inverted naturalnatural inverted natural inverted inverted inverted 52 inverted naturalinverted inverted natural natural inverted inverted 53 inverted naturalnatural inverted inverted natural inverted inverted 54 inverted naturalnatural natural inverted inverted inverted inverted 55 inverted naturalinverted natural natural inverted inverted inverted 56 inverted naturalinverted inverted inverted natural inverted inverted 57 inverted naturalnatural inverted inverted inverted inverted inverted 58 inverted naturalinverted natural inverted inverted inverted inverted 59 inverted naturalinverted inverted natural inverted inverted inverted 60 inverted naturalinverted inverted inverted inverted inverted inverted

TABLE 4 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 naturalinverted inverted natural natural natural natural natural 2 naturalinverted natural inverted natural natural natural natural 3 naturalinverted natural natural inverted natural natural natural 4 naturalinverted natural natural natural inverted natural natural 5 naturalinverted inverted natural inverted natural natural natural 6 naturalinverted natural inverted natural inverted natural natural 7 naturalinverted inverted inverted natural natural natural natural 8 naturalinverted natural natural inverted inverted natural natural 9 naturalinverted natural inverted inverted natural natural natural 10 naturalinverted inverted natural natural inverted natural natural 11 naturalinverted inverted inverted inverted natural natural natural 12 naturalinverted natural inverted inverted inverted natural natural 13 naturalinverted inverted natural inverted inverted natural natural 14 naturalinverted inverted inverted natural inverted natural natural 15 naturalinverted inverted inverted inverted inverted natural natural 16 naturalinverted inverted natural natural natural inverted natural 17 naturalinverted natural inverted natural natural inverted natural 18 naturalinverted natural natural inverted natural inverted natural 19 naturalinverted natural natural natural inverted inverted natural 20 naturalinverted inverted natural inverted natural inverted natural 21 naturalinverted natural inverted natural inverted inverted natural 22 naturalinverted inverted inverted natural natural inverted natural 23 naturalinverted natural inverted inverted natural inverted natural 24 naturalinverted natural natural inverted inverted inverted natural 25 naturalinverted inverted natural natural inverted inverted natural 26 naturalinverted inverted inverted inverted natural inverted natural 27 naturalinverted natural inverted inverted inverted inverted natural 28 naturalinverted inverted natural inverted inverted inverted natural 29 naturalinverted inverted inverted natural inverted inverted natural 30 naturalinverted inverted inverted inverted inverted inverted natural 31 naturalinverted inverted natural natural natural natural inverted 32 naturalinverted natural inverted natural natural natural inverted 33 naturalinverted natural natural inverted natural natural inverted 34 naturalinverted natural natural natural inverted natural inverted 35 naturalinverted inverted natural inverted natural natural inverted 36 naturalinverted natural inverted natural inverted natural inverted 37 naturalinverted inverted inverted natural natural natural inverted 38 naturalinverted natural inverted inverted natural natural inverted 39 naturalinverted natural natural inverted inverted natural inverted 40 naturalinverted inverted natural natural inverted natural inverted 41 naturalinverted inverted inverted inverted natural natural inverted 42 naturalinverted natural inverted inverted inverted natural inverted 43 naturalinverted inverted natural inverted inverted natural inverted 44 naturalinverted inverted inverted natural inverted natural inverted 45 naturalinverted inverted inverted inverted inverted natural inverted 46 naturalinverted inverted natural natural natural inverted inverted 47 naturalinverted natural inverted natural natural inverted inverted 48 naturalinverted natural natural inverted natural inverted inverted 49 naturalinverted natural natural natural inverted inverted inverted 50 naturalinverted inverted natural inverted natural inverted inverted 51 naturalinverted natural inverted natural inverted inverted inverted 52 naturalinverted inverted inverted natural natural inverted inverted 53 naturalinverted natural inverted inverted natural inverted inverted 54 naturalinverted natural natural inverted inverted inverted inverted 55 naturalinverted inverted natural natural inverted inverted inverted 56 naturalinverted inverted inverted inverted natural inverted inverted 57 naturalinverted natural inverted inverted inverted inverted inverted 58 naturalinverted inverted natural inverted inverted inverted inverted 59 naturalinverted inverted inverted natural inverted inverted inverted 60 naturalinverted inverted inverted inverted inverted inverted inverted

TABLE 5 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 invertedinverted inverted natural natural natural natural natural 2 invertedinverted natural inverted natural natural natural natural 3 invertedinverted natural natural inverted natural natural natural 4 invertedinverted natural natural natural inverted natural natural 5 invertedinverted inverted natural inverted natural natural natural 6 invertedinverted natural inverted natural inverted natural natural 7 invertedinverted inverted inverted natural natural natural natural 8 invertedinverted natural natural inverted inverted natural natural 9 invertedinverted natural inverted inverted natural natural natural 10 invertedinverted inverted natural natural inverted natural natural 11 invertedinverted inverted inverted inverted natural natural natural 12 invertedinverted natural inverted inverted inverted natural natural 13 invertedinverted inverted natural inverted inverted natural natural 14 invertedinverted inverted inverted natural inverted natural natural 15 invertedinverted inverted inverted inverted inverted natural natural 16 invertedinverted inverted natural natural natural inverted natural 17 invertedinverted natural inverted natural natural inverted natural 18 invertedinverted natural natural inverted natural inverted natural 19 invertedinverted natural natural natural inverted inverted natural 20 invertedinverted inverted natural inverted natural inverted natural 21 invertedinverted natural inverted natural inverted inverted natural 22 invertedinverted inverted inverted natural natural inverted natural 23 invertedinverted natural inverted inverted natural inverted natural 24 invertedinverted natural natural inverted inverted inverted natural 25 invertedinverted inverted natural natural inverted inverted natural 26 invertedinverted inverted inverted inverted natural inverted natural 27 invertedinverted natural inverted inverted inverted inverted natural 28 invertedinverted inverted natural inverted inverted inverted natural 29 invertedinverted inverted inverted natural inverted inverted natural 30 invertedinverted inverted inverted inverted inverted inverted natural 31inverted inverted inverted natural natural natural natural inverted 32inverted inverted natural inverted natural natural natural inverted 33inverted inverted natural natural inverted natural natural inverted 34inverted inverted natural natural natural inverted natural inverted 35inverted inverted inverted natural inverted natural natural inverted 36inverted inverted natural inverted natural inverted natural inverted 37inverted inverted inverted inverted natural natural natural inverted 38inverted inverted natural inverted inverted natural natural inverted 39inverted inverted natural natural inverted inverted natural inverted 40inverted inverted inverted natural natural inverted natural inverted 41inverted inverted inverted inverted inverted natural natural inverted 42inverted inverted natural inverted inverted inverted natural inverted 43inverted inverted inverted natural inverted inverted natural inverted 44inverted inverted inverted inverted natural inverted natural inverted 45inverted inverted inverted inverted inverted inverted natural inverted46 inverted inverted inverted natural natural natural inverted inverted47 inverted inverted natural inverted natural natural inverted inverted48 inverted inverted natural natural inverted natural inverted inverted49 inverted inverted natural natural natural inverted inverted inverted50 inverted inverted inverted natural inverted natural inverted inverted51 inverted inverted natural inverted natural inverted inverted inverted52 inverted inverted inverted inverted natural natural inverted inverted53 inverted inverted natural inverted inverted natural inverted inverted54 inverted inverted natural natural inverted inverted inverted inverted55 inverted inverted inverted natural natural inverted inverted inverted56 inverted inverted inverted inverted inverted natural invertedinverted 57 inverted inverted natural inverted inverted invertedinverted inverted 58 inverted inverted inverted natural invertedinverted inverted inverted 59 inverted inverted inverted invertednatural inverted inverted inverted 60 inverted inverted invertedinverted inverted inverted inverted inverted

In one embodiment, R^(a) and R^(b) are each methyl or trifluoromethyl.In another embodiment, one of R^(a) and R^(b) may be methyl ortrifluoromethyl and the other of R^(a) and R^(b) may be hydrogen. Inanother embodiment, both R^(a) and R^(b) may be hydrogen. In anotherembodiment, R^(a) and R^(b) are both methyl. In still anotherembodiment, R^(a) and R^(b) are methyl and the stereochemicalconfiguration of the carbon atom bearing them corresponds to thestereochemical configuration of PF1022A. In another embodiment, R^(a)and R^(b) are methyl and the stereochemical configuration of the carbonatom bearing them is inverted compared with the corresponding positionsof PF1022A.

In one embodiment, the invention provides compounds wherein at least oneof the carbon atoms bearing —CH₂Cy¹ or —CH₂Cy² are inverted comparedwith the stereochemical configuration of PF1022A. In another embodiment,the stereochemical configuration of both carbon atoms bearing —CH₂Cy¹and —CH₂Cy² are inverted compared with PF1022A. In another embodiment,the invention provides compounds wherein the carbon atoms bearing—CH₂Cy¹ or —CH₂Cy² are inverted compared with the stereochemicalconfiguration of PF1022A and the carbon atoms bearing R¹, R², R³ and R⁴have the natural stereochemical configuration relative to PF1022A. Inanother embodiment, the stereochemical configuration of both carbonatoms bearing —CH₂Cy¹ and —CH₂Cy² are inverted compared with PF1022A andthe carbon atoms bearing R¹, R², R³ and R⁴ have the naturalstereochemical configuration relative to PF1022A.

In yet another embodiment, the invention provides compounds wherein thecarbon atoms bearing —CH₂Cy¹ or —CH₂Cy² are inverted compared withPF1022A and the stereochemical configuration of one of the carbonsbearing R¹, R², R³ and R⁴ is also inverted. In another embodiment, theinvention provides compounds wherein the carbon atoms bearing —CH₂Cy¹ or—CH₂Cy² are inverted compared with PF1022A and the stereochemicalconfiguration of two of the carbons bearing R¹, R², R³ and R⁴ is alsoinverted. In another embodiment, the invention provides compoundswherein the carbon atoms bearing —CH₂Cy¹ or —CH₂Cy² are invertedcompared with PF1022A and the stereochemical configuration of three ofthe carbons bearing R¹, R², R³ and R⁴ is also inverted. In yet anotherembodiment, the invention provides compounds wherein the carbon atomsbearing —CH₂Cy¹ or —CH₂Cy² are inverted compared with PF1022A and thestereochemical configuration of all four of the carbons bearing R¹, R²,R³ and R⁴ is also inverted.

In another embodiment, the stereochemical configuration of both carbonatoms bearing —CH₂Cy¹ and —CH₂Cy² are the same as the correspondingcarbon atoms of PF1022A and the stereochemical configuration of one ofcarbon atoms bearing R¹, R², R³ and R⁴ is inverted relative to PF1022A.In another embodiment, the stereochemical configuration of both carbonatoms bearing —CH₂Cy¹ and —CH₂Cy² are the same as the correspondingcarbon atoms of PF1022A and the stereochemical configuration of two ofcarbon atoms bearing R¹, R², R³ and R⁴ is inverted relative to PF1022A.In yet another embodiment, the stereochemical configuration of bothcarbon atoms bearing —CH₂Cy¹ and —CH₂Cy² are the same as thecorresponding carbon atoms of PF1022A and the stereochemicalconfiguration of three of carbon atoms bearing R¹, R², R³ and R⁴ isinverted relative to PF1022A. In still another embodiment, thestereochemical configuration of both carbon atoms bearing —CH₂Cy¹ and—CH₂Cy² are the same as the corresponding carbon atoms of PF1022A andthe stereochemical configuration of one of all four of the carbon atomsbearing R¹, R², R³ and R⁴ are inverted relative to PF1022A.

In another embodiment, the stereochemical configuration of at least oneof the carbon atoms bearing R^(a) and R^(b) are inverted compared withthe corresponding carbon atoms of PF1022A. In another embodiment, thestereochemical configuration of both of the carbon atoms bearing R^(a)and R^(b) are inverted compared with corresponding carbon atoms inPF1022A.

In yet another embodiment, the invention provides compounds wherein atleast one of the carbon atoms bearing —CH₂Cy¹ or —CH₂Cy² and at leastone of the carbon atoms bearing R^(a) and R^(b) are are invertedcompared with PF1022A and the stereochemical configuration of thecarbons bearing R¹, R², R³ and R⁴ are in the same stereochemicalconfiguration as the corresponding carbon atoms in PF1022A. In anotherembodiment, least one of the carbon atoms bearing R¹, R², R³ and R⁴ andat least one of the carbon atoms bearing R^(a) and R^(b) are areinverted compared with PF1022A and the stereochemical configuration ofthe carbons bearing Cy¹ and Cy² are in the same stereochemicalconfiguration as the corresponding carbon atoms in PF1022A. In anotherembodiment, least one of the carbon atoms bearing R¹, R², R³ and R⁴ andat least one of the carbon atoms bearing R^(a) and R^(b) and at leastone of the carbon atoms bearing Cy¹ and Cy² are are inverted comparedwith PF1022A.

Cy¹ and Cy² Groups

In various embodiments of the invention, the groups Cy¹ and Cy² in thecompounds of formula (I) with the stereochemical configuration describedin Tables 1 to 5 above are further described below. It will beappreciated that type of groups described for Cy¹ and Cy² may beincluded in any compounds having the stereochemical configurationdefined in Tables 1 to 5. In one embodiment, Cy¹ and Cy² in each of thecompounds of formula (I) with the stereochemical configuration describedin Tables 1-5 above are independently phenyl optionally substituted withone or more substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S— heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵ and R⁶ are as defined above forformula (I).

In another embodiment, Cy¹ and Cy² in the compounds of formula (I) areindependently phenyl, heteroaryl or heterocyclyl optionallyindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclyl or—S-heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵and R⁶ are as defined above for formula (I).

In another embodiment, Cy¹ and Cy² in each of the compounds of formula(I) are independently 6-12 membered bicyclic aryl or heteroaryl groupsoptionally substituted with one or more substituents selected from thegroup consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclyl or—S-heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵and R⁶ are as defined above for formula (I).

In another embodiment, Cy¹ and Cy² are independently bicyclicheterocyclic groups optionally substituted with one or more substituentsselected from the group consisting of halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino,dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O—heterocyclyl or —S-heterocyclyl, wherein each cycloalkyl, heteroalkyl,aryl or heteroaryl is optionally further independently substituted withone or more substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵and R⁶ are as defined above for formula (I).

In another embodiment, Cy¹ and Cy² are independently phenyl, biphenyl,naphthyl, tetrahydronaphthyl, phenylcyclopropyl, biphenylene, fluorene,anthracene, acenaphthene, phenanthrene or indanyl optionally substitutedwith one or more substituents selected from the group consisting ofhalogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵ and R⁶ are as defined above forformula (I).

In yet another embodiment, Cy¹ and Cy² are independently pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl,thiophenyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl,pyrazolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,imidazopyridyl, imidazopyrimidyl or pyrrolopyrimidyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclyl or—S-heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵and R⁶ are as defined above for formula (I).

In another embodiment, Cy¹ and Cy² are independently pyrrolidinyl,pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl or triazinyloptionally independently substituted with one or more substituentsselected from the group consisting of halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino,dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, —O-heteroaryl, —S-heteroaryl,—O-heterocyclyl or —S-heterocyclyl, wherein each cycloalkyl,heteroalkyl, aryl or heteroaryl is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵ and R⁶ are as defined above forformula (I).

In another embodiment, Cy¹ and Cy² are independently indolyl,isoindolyl, benzothiazolyl, benzoxazolyl, benz[d]isoxazolyl,benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl,1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl ortetrahydroisoquinolinyl optionally substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵ and R⁶ are as defined above forformula (I).

In one embodiment, Cy¹ and Cy² are independently phenyl substituted withheterocyclyl. In yet another embodiment, Cy¹ and Cy² are independently a6-membered heteroaryl group substituted with heterocyclyl. In stillanother embodiment, Cy¹ and Cy² are independently heterocyclylsubstituted with a heterocyclyl group. In yet another embodiment, Cy¹and Cy² are independently phenyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl or tetrazinyl substituted with heterocyclyl.

In one embodiment, Cy¹ and Cy² are independently phenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl or tetrazinyl substituted withmorpholino, tetrahydropyran, tetrahydrofuran, pyrrolidino or piperidino.

In one embodiment, Cy¹ and Cy² are independently phenyl, a 5-membered ora 6-membered heteroaryl ring optionally substituted with halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, —SF₅,amino, alkylamino or dialkylamino.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withC₁-C₃alkyl, C₁-C₃haloalkyl, C₂-C₄alkenyl, C₂-C₄haloalkenyl,C₂-C₄alkynyl, C₂-C₄haloalkynyl, C₁-C₃alkoxy, C₁-C₃haloalkoxy,C₁-C₃alkylthio, C₁-C₃haloalkylthio, C₁-C₃alkylamino orC₁-C₃dialkylamino.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, CF₃,—CH₂CF₃, —CHFCF₃ or —CF₂CF₃.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withfluoro, chloro, bromo or iodo.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withhydroxy, methoxy, trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, —SCH₃,—SCF₃, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃, —S(O)CH₃, —S(O)CF₃, —S(O)CH₂CF₃,—S(O)CHFCF₃, —S(O)CF₂CF₃, —S(O)₂CH₃, —S(O)₂CF₃, —S(O)₂CH₂CF₃,—S(O)₂CHFCF₃, —S(O)₂CF₂CF₃ or SF₅.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl optionally substituted with halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino ordialkylamino.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl optionally substituted with alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl optionally substituted with C₁-C₃alkyl, C₁-C₃haloalkyl,C₂-C₄alkenyl, C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₂-C₄haloalkynyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio,C₁-C₃alkylamino or C₁-C₃dialkylamino.

In another embodiment, Cy¹ and Cy² are independently phenyl, a5-membered or a 6-membered heteroaryl ring optionally substituted withmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, CF₃,—CH₂CF₃, —CHFCF₃ or —CF₂CF₃.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl optionally substituted with fluoro, chloro, bromo or iodo.

In yet another embodiment, Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl optionally substituted with hydroxy, methoxy,trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, —SCH₃, —SCF₃, —SCH₂CF₃,—SCHFCF₃ or —SCF₂CF₃, —S(O)CH₃, —S(O)CF₃, —S(O)CH₂CF₃, —S(O)CHFCF₃,—S(O)CF₂CF₃, —S(O)₂CH₃, —S(O)₂CF₃, —S(O)₂CH₂CF₃, —S(O)₂CHFCF₃,—S(O)₂CF₂CF₃ or SF₅.

In another embodiment, Cy¹ and Cy² are independently one of R1 to R8shown below:

wherein Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C,CH or N; and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,cycloalkyl, heteroalkyl, heterocyclyl, aryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, heteroaryl, whereineach cycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furthersubstituted with one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵ and R⁶ are as defined above forformula (I).

In one embodiment, Cy¹ and Cy² are independently R1 to R8 wherein Y¹,Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N; andX¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, thioamido, amino, alkylamino or dialkylamino.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, CF₃, —CH₂CF₃,—CHFCF₃ or CF₂CF₃.

In another embodiment, Cy¹ and Cy² are independently R1 to R8 whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, fluoro,chloro, bromo or iodo.

In another embodiment, Cy¹ and Cy² are independently R1 to R8, whereinY¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C, CH or N;and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, hydroxy,methoxy, trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, methylthio,trifluoromethylthio, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃ or SF₅.

In another embodiment, Cy¹ and Cy² are independently R9 to R11 shownbelow:

wherein X¹, X² and X³ are independently hydrogen, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, —O-heteroaryl, —S-heteroaryl,—O-heterocyclyl or —S-heterocyclyl, heteroaryl, wherein each cycloalkyl,heteroalkyl, aryl or heteroaryl is optionally further substituted withone or more substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂, wherein R⁵and R⁶ are as defined above for formula (I).

In one embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, halogen, alkyl or haloalkyl. Inanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, fluoro, chloro, bromo or iodo. Inanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, CF₃, —CH₂CF₃, —CHFCF₃ or CF₂CF₃. In yetanother embodiment, Cy¹ and Cy² are independently R9 to R11, wherein X¹,X² and X³ are independently hydrogen, hydroxy, methoxy,trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, methylthio,trifluoromethylthio, —SCH₂CF₃, —SCHFCF₃, —SCF₂CF₃ or SF₅.

In another embodiment, Cy¹ and/or Cy² are independently phenyl,p-morpholinophenyl, p-fluorophenyl, p-trifluoromethoxyphenyl,p-trifluoromethylthiophenyl, p-CF₃-phenyl, 3,4,5-trifluoro-phenyl,p-tetrahydropyranyl-4-yl-phenyl, 2-(morpholin-4-yl)pyridine-5-yl,5-(morpholin-4-yl)pridin-2-yl, p-thiosulfonylmorpholin-4-yl-phenyl,p-NH₂-phenyl, p-(1-Me-1H-tetrazole-5-thiolyl)phenyl, p-NH₂-phenyl,2,3-dihydrobenzofuran-5-yl, 4-(morpholin-4-yl)cyclylhexanyl,p-iodophenyl, p-bromophenyl, p-nitrophenyl and p-tert-butylphenyl.

In another embodiment, Cy¹ and Cy² are the groups shown in Table 6below:

TABLE 6 Cy¹ Cy²

Ph p-F—Ph p-F—Ph p-OCF₃—Ph p-OCF₃—Ph p-SCF₃—Ph p-SCF₃—Ph Ph Ph p-CF₃—Php-CF₃—Ph 3,4,5-tri-F—Ph 3,4,5-tri-F—Ph

p-NH₂—Ph p-NH₂—Ph

p-I—Ph

p-I—Ph p-I—Ph p-Br—Ph p-Br—Ph p-NO₂—Ph p-NO₂—Ph

Ph p-tBu—Ph p-tBu—Ph p-SF₅—Ph p-SF₅—Ph

R^(a) and R^(b)

R^(a) and R^(b) in the compounds of formula (I) with the stereochemicalconfiguration described in Tables 1 to 5 above may independently behydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In one embodiment, R^(a) and R^(b) are independently hydrogen or methyl.In another embodiment, R^(a) and R^(b) are independently hydrogen,methyl, ethyl or propyl. In another embodiment, R^(a) and R^(b) areindependently hydrogen, methyl or CF₃. In still another embodiment,R^(a) and R^(b) are both methyl. In yet another embodiment, R^(a) andR^(b) are both hydrogen.

R′, R″, R″′ and R″″

In one embodiment, each of R′, R″, R″′ and R″″ are independentlyhydrogen or C₁-C₃alkyl. In another embodiment, each of R′, R″, R″′ andR″″ are independently hydrogen or methyl. In another embodiment, each ofR′, R″, R″′ and R″″ are independently hydrogen, methyl or ethyl.

R¹, R², R³ and R⁴

It will be understood that the invention includes compounds wherein thevarious groups Cy¹ and Cy² described in the above embodiments with thestereochemical configuration defined in Tables 1 to 5 are combined withany combination of R¹, R², R³ and R⁴ described above for formula (I) andin the embodiments described below.

In one embodiment of the invention, one of R¹ to R⁴ is a C₁-C₈ alkylgroup substituted by one or more of the substituents for these variablesdescribed above for formula (I) while the others of R¹ to R⁴ areunsubstituted C₁-C₈ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₈ alkyl independentlysubstituted by one or more of the substituents for these variablesdescribed above for formula (I) while the other two of R¹ to R⁴ areunsubstituted C₁-C₈ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₈alkylindependently substituted by one or more of the substituents for thesevariables described above for formula (I) while the other of R¹ to R⁴ isunsubstituted C₁-C₈ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₈ alkylindependently substituted by one or more of the substituents for thesevariables described above for formula (I).

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more of the substituents for these variablesdescribed above for formula (I) while the others of R¹ to R⁴ areunsubstituted C₁-C₆ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more of the substituents for these variablesdescribed above for formula (I) while the other two of R¹ to R⁴ areunsubstituted C₁-C₆ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more of the substituents for thesevariables described above for formula (I) while the other of R¹ to R⁴ isunsubstituted C₁-C₆ alkyl.

In still another embodiment, all four of R¹ to R⁴ are independentlyC₁-C₆alkyl substituted by one or more of the substituents for thesevariables described above for formula (I).

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more of the substituents for these variablesdescribed above for formula (I) while the others of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more of the substituents for these variablesdescribed above for formula (I) while the other two of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more of the substituents for thesevariables described above for formula (I) while the other of R¹ to R⁴ isunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₈ alkylgroup substituted by one or more halogen while the others of R¹ to R⁴are unsubstituted C₁-C₈ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₈ alkyl independentlysubstituted by one or more halogen while the other two of R¹ to R⁴ areunsubstituted C₁-C₈ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₈ alkylindependently substituted by one or more halogen while the other of R¹to R⁴ is unsubstituted C₁-C₈ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₈ alkylindependently substituted one or more halogen.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more halogen while the others of R¹ to R⁴are unsubstituted C₁-C₆ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more halogen while the other two of R¹ to R⁴ areunsubstituted C₁-C₆ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more halogen while the other of R¹to R⁴ is unsubstituted C₁-C₆ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₆alkylindependently substituted one or more halogen.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more halogen while the others of R¹ to R⁴are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more halogen while the other two of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more halogen while the other of R¹to R⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₈ alkylgroup substituted by one or more fluoro while the others of R¹ to R⁴ areunsubstituted C₁-C₈ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₈ alkyl independentlysubstituted by one or more fluoro while the other two of R¹ to R⁴ areunsubstituted C₁-C₈ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₈ alkylindependently substituted by one or more fluoro while the other of R¹ toR⁴ is unsubstituted C₁-C₈ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₈ alkylindependently substituted one or more fluoro.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more fluoro while the others of R¹ to R⁴ areunsubstituted C₁-C₆ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more fluoro while the other two of R¹ to R⁴ areunsubstituted C₁-C₆ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more fluoro while the other of R¹ toR⁴ is unsubstituted C₁-C₆ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₆alkylindependently substituted one or more fluoro.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more fluoro while the others of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more fluoro while the other two of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more fluoro while the other of R¹ toR⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In one embodiment of the invention, one of R¹ to R⁴ is CH₂F, CHF₂ orCF₃; and the others of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl. In another embodiment, two of R¹ to R⁴ are CH₂F,CHF₂ or CF₃; and the other two of R¹ to R⁴ are unsubstituted2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are CH₂F, CHF₂ or CF₃; andthe other of R¹ to R⁴ is unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are CH₂F, CHF₂ or CF₃.

In one embodiment of the invention, one of R¹ to R⁴ is —CH₂CX(CH₃)₂wherein X is halogen; and the others of R¹ to R⁴ are unsubstituted2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are —CH₂CX(CH₃)₂ wherein X ishalogen; and the other two of R¹ to R⁴ are unsubstituted 2-methylpropylor 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are —CH₂CX(CH₃)₂ wherein Xis halogen; and the other of R¹ to R⁴ is unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are —CH₂CX(CH₃)₂ whereinX is halogen.

In one embodiment of the invention, one of R¹ to R⁴ is —CH₂CF(CH₃)₂; andthe others of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are —CH₂CF(CH₃)₂; and the othertwo of R¹ to R⁴ are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are —CH₂CF(CH₃)₂; and theother of R¹ to R⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are —CH₂CF(CH₃)₂.

In another embodiment of the invention, one of R¹ to R⁴ is —CH₂CX(CH₃)₂wherein X is CH₂F, CHF₂ or CF₃; and the others of R¹ to R⁴ areunsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are —CH₂CX(CH₃)₂ wherein X isCH₂F, CHF₂ or CF₃; and the other two of R¹ to R⁴ are unsubstituted2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are —CH₂CX(CH₃)₂ wherein Xis CH₂F, CHF₂ or CF₃; and the other of R¹ to R⁴ is unsubstituted2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are —CH₂CX(CH₃)₂ whereinX is CH₂F, CHF₂ or CF₃.

In one embodiment of the invention, one of R¹ to R⁴ is a C₁-C₈ alkylgroup substituted by one or more aryl or heteroaryl groups while theothers of R¹ to R⁴ are unsubstituted C₁-C₈ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₈ alkyl independentlysubstituted by one or more aryl or heteroaryl groups while the other twoof R¹ to R⁴ are unsubstituted C₁-C₈ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₈ alkylindependently substituted by one or more aryl or heteroaryl groups whilethe other of R¹ to R⁴ is unsubstituted C₁-C₈ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₈ alkylindependently substituted one or more aryl or heteroaryl groups.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more aryl or heteroaryl groups while theothers of R¹ to R⁴ are unsubstituted C₁-C₆ alkyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more aryl or heteroaryl groups while the other twoof R¹ to R⁴ are unsubstituted C₁-C₆ alkyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more aryl or heteroaryl groups whilethe other of R¹ to R⁴ is unsubstituted C₁-C₆ alkyl.

In still another embodiment, all four of R¹ to R⁴ are C₁-C₆alkylindependently substituted one or more aryl or heteroaryl groups.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by one or more aryl or heteroaryl groups while theothers of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are C₁-C₆alkyl independentlysubstituted by one or more aryl or heteroaryl groups while the other twoof R¹ to R⁴ are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are C₁-C₆alkylindependently substituted by one or more aryl or heteroaryl groups whilethe other of R¹ to R⁴ is unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by an optionally substituted phenyl while the othersof R¹ to R⁴ are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are independently C₁-C₆alkylsubstituted by an optionally substituted phenyl while the other two ofR¹ to R⁴ are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are independentlyC₁-C₆alkyl substituted by an optionally substituted phenyl while theother of R¹ to R⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are independentlyC₁-C₆alkyl substituted by an optionally substituted phenyl.

In another embodiment of the invention, one of R¹ to R⁴ is a C₁-C₆ alkylgroup substituted by an optionally substituted heteroaryl group selectedfrom the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl while theothers of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are independently C₁-C₆alkylsubstituted by an optionally substituted heteroaryl group selected fromthe group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl while theother two of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are independentlyC₁-C₆alkyl substituted by an optionally substituted heteroaryl groupselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl while theother of R¹ to R⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are independentlyC₁-C₆alkyl substituted by an optionally substituted heteroaryl groupselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.

In another embodiment of the invention, one, two, three or all four ofR¹ to R⁴ is the group G-1:

wherein R^(1A), R^(1B), R^(1C), R^(1D) and R^(1E) are independentlyhydrogen, halogen, alkyl or haloalkyl; and the others of R¹ to R⁴, ifapplicable, are unsubstituted C₁-C₈ alkyl.

In one embodiment of the invention, one of R¹ to R⁴ is G-1; and theothers of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, two of R¹ to R⁴ are G-1; and the other two of R¹to R⁴ are unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, three of R¹ to R⁴ are G-1; and the other ofR¹ to R⁴ is unsubstituted 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, all four of R¹ to R⁴ are G-1.

In one embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A), R^(1B)R^(1C), R^(1D) and R^(1E) are independentlyhydrogen, fluoro, C₁-C₃ alkyl or C₁-C₃ haloalkyl and the others of R¹ toR⁴ are unsubstituted C₁-C₆alkyl. In another embodiment, one, two, threeor all four of R¹ to R⁴ are G-1, wherein R^(1A), R^(1B), R^(1C), R^(1D)and R^(1E) are independently hydrogen, fluoro, C₁-C₃ alkyl or C₁-C₃haloalkyl and the others of R¹ to R⁴ are unsubstituted 2-methylpropyl or2,2-dimethylpropyl.

In one embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1D) and R^(1E) are independently H or halogen. In anotherembodiment, one, two, three or all four of R¹ to R⁴ are G-1, whereinR^(1D) and R^(1E) are independently C₁-C₃ alkyl or C₁-C₃ haloalkyl. Inanother embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is H or halogen. In another embodiment, one, two, threeor all four of R¹ to R⁴ are G-1, wherein R^(1A) is C₁-C₃ alkyl or C₁-C₃haloalkyl. In another embodiment, one, two, three or all four of R¹ toR⁴ are G-1, wherein R^(1A) is halogen, and R^(1B) and R^(1C) areindependently C₁-C₃ alkyl or C₁-C₃ haloalkyl. In yet another embodiment,one, two, three or all four of R¹ to R⁴ are G-1, wherein R^(1D) andR^(1E) are H, R^(1A) is halogen, and R^(1B) and R^(1C) are independentlyC₁-C₃ alkyl or C₁-C₃ haloalkyl.

In one embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1D) and R^(1E) are independently H or F. In anotherembodiment, one, two, three or all four of R¹ to R⁴ are G-1, whereinR^(1D) and R^(1E) are independently methyl or trifluoromethyl. Inanother embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is H or F. In another embodiment, one, two, three or allfour of R¹ to R⁴ are G-1, wherein R^(1A) is methyl or trifluoromethyl.In another embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl. In yet another embodiment, one, two, three or all fourof R¹ to R⁴ are G-1, wherein R^(1D) and R^(1E) are H, R^(1A) is F,R^(1B) and R^(1C) are methyl or trifluoromethyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is C₁-C₃ alkyl or C₁-C₃ haloalkyl; and the other of R¹ toR⁴ are 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is halogen, and R^(1B) and R^(1C) are independently C₁-C₃alkyl or C₁-C₃ haloalkyl; and the other of R¹ to R⁴ are 2-methylpropylor 2,2-dimethylpropyl. In yet another embodiment, one, two, three or allfour of R¹ to R⁴ are G-1, wherein R^(1D) and R^(1E) are H, R^(1A) ishalogen, and R^(1B) and R^(1C) are independently C₁-C₃ alkyl or C₁-C₃haloalkyl; and the other of R¹ to R⁴ are 2-methylpropyl or2,2-dimethylpropyl.

In one embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein one of R^(1D) and R^(1E) is F; and the others of R¹ to R⁴ are2-methylpropyl or 2,2-dimethylpropyl. In another embodiment, one, two,three or all four of R¹ to R⁴ are G-1, wherein one of R^(1D) and R^(1E)is methyl or trifluoromethyl; and the others of R¹ to R⁴ are2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is F; and the others of R¹ to R⁴ are 2-methylpropyl or2,2-dimethylpropyl. In another embodiment, one, two, three or all fourof R¹ to R⁴ are G-1, wherein R^(1A) is methyl or trifluoromethyl; andthe others of R¹ to R⁴ are 2-methylpropyl or 2,2-dimethylpropyl. Inanother embodiment, one, two, three or all four of R¹ to R⁴ are G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and the others of R¹ to R⁴ are 2-methylpropyl or2,2-dimethylpropyl. In yet another embodiment, one, two, three or allfour of R¹ to R⁴ are G-1, wherein R^(1D) and R^(1E) are H, R^(1A) is F,R^(1B) and R^(1C) are methyl or trifluoromethyl; and the others of R¹ toR⁴ are 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, one of R¹ to R⁴ are G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and the others of R¹ toR⁴ are 2-methylpropyl or 2,2-dimethylpropyl. In another embodiment, twoof R¹ to R⁴ are G-1, wherein R^(1A) is F, and R^(1B) and R^(1C) aremethyl or trifluoromethyl; and the others of R¹ to R⁴ are 2-methylpropylor 2,2-dimethylpropyl. In another embodiment, three of R¹ to R⁴ are G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and the others of R¹ to R⁴ are 2-methylpropyl or2,2-dimethylpropyl. In another embodiment, all four of R¹ to R⁴ are G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl. In one embodiment, R¹ is G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and R², R³ and R⁴ are2-methylpropyl or 2,2-dimethylpropyl. In another embodiment, R² is G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R², R³ and R⁴ are 2-methylpropyl or2,2-dimethylpropyl. In yet another embodiment, R³ is G-1, wherein R^(1A)is F, and R^(1B) and R^(1C) are methyl or trifluoromethyl; and R¹, R²and R⁴ are 2-methylpropyl or 2,2-dimethylpropyl. In another embodiment,R⁴ is G-1, wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R¹, R² and R³ are 2-methylpropyl or2,2-dimethylpropyl.

In another embodiment, R¹ and R³ are G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and R² and R⁴ are2-methylpropyl or 2,2-dimethylpropyl. In another embodiment, R² and R⁴are G-1, wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R¹ and R³ are 2-methylpropyl or 2,2-dimethylpropyl.In another embodiment, R¹ and R² are G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and R³ and R⁴ are2-methylpropyl or 2,2-dimethylpropyl. In yet another embodiment, R² andR³ are G-1, wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R¹ and R⁴ are 2-methylpropyl or 2,2-dimethylpropyl.In another embodiment, R¹ and R⁴ are G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and R² and R³ are2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, R¹, R² and R³ are G-1, wherein R^(1A) is F, andR^(1B) and R¹c are methyl or trifluoromethyl; and R⁴ is 2-methylpropylor 2,2-dimethylpropyl. In another embodiment, R¹, R² and R⁴ are G-1,wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R³ is 2-methylpropyl or 2,2-dimethylpropyl. Inanother embodiment, R¹, R³ and R⁴ are G-1, wherein R^(1A) is F, andR^(1B) and R^(1C) are methyl or trifluoromethyl; and R² is2-methylpropyl or 2,2-dimethylpropyl. In another embodiment, R², R³ andR⁴ are G-1, wherein R^(1A) is F, and R^(1B) and R^(1C) are methyl ortrifluoromethyl; and R¹ is 2-methylpropyl or 2,2-dimethylpropyl.

In one embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or naphthyl substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R¹ and R³ are independently C₁-C₆ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; R² and R⁴ are independently unsubstituted C₁-C₆ alkyl; andR⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or naphthyl substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,alkyl, haloalkyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heterocyclyl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclylor —S— heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl; and

R¹ and R³ are independently C₁-C₆ alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R² and R⁴ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl or the group—CH₂C(O)NHCH₂CF₃.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkyl,C₁-C₃haloalkyl, R⁵R⁶NC(O)—, phenyl, C₃-C₆cycloalkyl, C₄-C₆heterocyclyl,C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl,—O—C₄-C₆heterocyclyl or —S—C₄-C₆heterocyclyl, wherein each cycloalkyl,heterocyclyl, phenyl or heteroaryl is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, CN, NO₂, SF₅, alkoxy, haloalkoxy, alkylthio,haloalkylthio, amino, alkylamino, dialkylamino, C₁-C₃alkyl orC₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen;

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, CN, NO₂,SF₅, C₁-C₃alkyl, C₁-C₃haloalkyl, C₃-C₆cycloalkyl, morpholino,tetrahydropyran, tetrahydrofuran, piperidino or pyrrolidino, whereineach C₃-C₆cycloalkyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylamino, dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl, —S—tetrazolyl or pyrrolidinyl, wherein each cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CF(CH₃)₂; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In one embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or naphthyl substituted with one ormore substituents selected from the group consisting of halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R² and R⁴ are independently C₁-C₆ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino;

R¹ and R³ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or naphthyl substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,alkyl, haloalkyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heterocyclyl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclylor —S— heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R² and R⁴ are independently C₁-C₆ alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R¹ and R³ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl or the group—CH₂C(O)NHCH₂CF₃.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkyl,C₁-C₃haloalkyl, R⁵R⁶NC(O)—, phenyl, C₃-C₆cycloalkyl, C₄-C₆heterocyclyl,C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl,—O—C₄-C₆heterocyclyl or —S—C₄-C₆heterocyclyl, wherein each cycloalkyl,heterocyclyl, phenyl or heteroaryl is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, CN, NO₂, SF₅, alkoxy, haloalkoxy, alkylthio,haloalkylthio, amino, alkylamino, dialkylamino, C₁-C₃alkyl orC₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen;

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, CN, NO₂,SF₅, C₁-C₃alkyl, C₁-C₃haloalkyl, C₃-C₆cycloalkyl, morpholino,tetrahydropyran, tetrahydrofuran, piperidino or pyrrolidino, whereineach C₃-C₆cycloalkyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylamino, dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen;

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl, —S—tetrazolyl or pyrrolidinyl, wherein each cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently —CH₂CF(CH₃)₂; and

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In one embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl; and

R¹ and R³ are independently C₁-C₆ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino;

R² and R⁴ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,alkyl, haloalkyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heterocyclyl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclylor —S-heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R¹ and R³ are independently C₁-C₆ alkyl substituted by one or more aryl,heteroaryl, heterocyclyl or halogen;

R² and R⁴ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl or the group—CH₂C(O)NHCH₂CF₃.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, phenyl, C₃-C₆cycloalkyl,C₄-C₇heterocyclyl, C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl,—S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or —S—C₄-C₇heterocyclyl,wherein each cycloalkyl, heterocyclyl, phenyl or heteroaryl isoptionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl or tetrazinyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkyl,C₁-C₃haloalkyl, R⁵R⁶NC(O)—, phenyl, C₃-C₆cycloalkyl, C₄-C₆heterocyclyl,C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl,—O—C₄-C₆heterocyclyl or —S—C₄-C₆heterocyclyl, wherein each cycloalkyl,heterocyclyl, phenyl or heteroaryl is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, CN, NO₂, SF₅, alkoxy, haloalkoxy, alkylthio,haloalkylthio, amino, alkylamino, dialkylamino, C₁-C₃alkyl orC₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen;

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, SF₅, C₁-C₃alkyl, C₁-C₃haloalkyl,C₃-C₆cycloalkyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino, wherein each C₃-C₆cycloalkyl, morpholino,tetrahydropyran, tetrahydrofuran, piperidino or pyrrolidino isoptionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl, —S—tetrazolyl or pyrrolidinyl, wherein each cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R³ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently pyridyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R³ are independently —CH₂CF(CH₃)₂; and

R² and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In one embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, —O-heteroaryl,—S-heteroaryl, —O-heterocyclyl or —S-heterocyclyl, wherein eachcycloalkyl, heteroalkyl, aryl or heteroaryl is optionally furtherindependently substituted with one or more substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN and —NO₂;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R² and R⁴ are independently C₁-C₆ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino;

R¹ and R³ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵ and R⁶together with the atom(s) to which they are bonded form a C₃-C₆ cyclicgroup.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,alkyl, haloalkyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl,heterocyclyl, heteroaryl, —O-heteroaryl, —S-heteroaryl, —O-heterocyclylor —S-heterocyclyl, wherein each cycloalkyl, heteroalkyl, aryl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or C₁-C₃alkyl;

R² and R⁴ are independently C₁-C₆ alkyl substituted by one or more aryl,heteroaryl, heterocyclyl or halogen;

R¹ and R³ are independently unsubstituted C₁-C₆ alkyl; and

R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl or the group—CH₂C(O)NHCH₂CF₃.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl substitutedwith one or more substituents selected from the group consisting ofhalogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, phenyl, C₃-C₆cycloalkyl,C₄-C₇heterocyclyl, C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl,—S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or —S—C₄-C₇heterocyclyl,wherein each cycloalkyl, heterocyclyl, phenyl or heteroaryl isoptionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl or tetrazinyl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkyl,C₁-C₃haloalkyl, R⁵R⁶NC(O)—, phenyl, C₃-C₆cycloalkyl, C₄-C₆heterocyclyl,C₅-C₆heteroaryl, —O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl,—O—C₄-C₆heterocyclyl or —S—C₄-C₆heterocyclyl, wherein each cycloalkyl,heterocyclyl, phenyl or heteroaryl is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, CN, NO₂, SF₅, alkoxy, haloalkoxy, alkylthio,haloalkylthio, amino, alkylamino, dialkylamino, C₁-C₃alkyl orC₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen;

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridinyl, pyrimidinyl, pyridazinyl, orpyrazinyl substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, SF₅, C₁-C₃alkyl, C₁-C₃haloalkyl,C₃-C₆cycloalkyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino, wherein each C₃-C₆cycloalkyl, morpholino,tetrahydropyran, tetrahydrofuran, piperidino or pyrrolidino isoptionally further independently substituted with one or moresubstituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently pyridyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl, —S—tetrazolyl or pyrrolidinyl, wherein each cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, morpholino, tetrahydropyran, tetrahydrofuran,piperidino or pyrrolidino is optionally further independentlysubstituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio,C₁-C₃haloalkylthio, amino, C₁-C₃alkylamino, C₁-C₃dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R⁴ are independently —CH₂CX(CH₃)₂ wherein X is halogen; and

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently pyridyl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R⁴ are independently —CH₂CF(CH₃)₂; and

R¹ and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R² are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R³ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R³ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R¹ and R² are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R¹ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R² and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R² are —CH₂CF(CH₃)₂; and

R³ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R³ and R⁴ are —CH₂CF(CH₃)₂; and

R¹ and R² are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R² and R³—CH₂CF(CH₃)₂; and

R¹ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹ and R⁴ are —CH₂CF(CH₃)₂; and

R² and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹, R² and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl; R⁴ is 2-methylpropyl or2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R³ is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R³ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R² is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R², R³ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, aryl, heteroaryl or heterocyclyl;

R¹ is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R³ are —CH₂CF(CH₃)₂; and

R⁴ is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R⁴ are —CH₂CF(CH₃)₂; and

R³ is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R³ and R⁴ are —CH₂CF(CH₃)₂; and

R² is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R², R³ and R⁴ are —CH₂CF(CH₃)₂; and

R¹ is 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹, R², R³ and R⁴ are independently C₁-C₆alkyl substituted by one ormore halogen, aryl, heteroaryl or heterocyclyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently heteroaryl substituted with one or moresubstituents selected from the group consisting of halogen, NO₂, SF₅,methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹, R², R³ and R⁴ are each —CH₂CF(CH₃)₂.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R² are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R³ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R³ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R¹ and R² are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R¹ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R⁴ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R² and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R² are —CH₂CF(CH₃)₂; and

R³ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R³ and R⁴ are —CH₂CF(CH₃)₂; and

R¹ and R² are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R² and R³—CH₂CF(CH₃)₂; and

R¹ and R⁴ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹ and R⁴—CH₂CF(CH₃)₂; and

R² and R³ are independently 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R³ are independently C₁-C₆alkyl substituted by one or morehalogen, optionally substituted phenyl or an optionally substitutedheteroaryl selected from the group consisting of thienyl, oxazolyl,isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl andtetrazinyl;

R⁴ is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R⁴ are independently C₁-C₆alkyl substituted by halogen,optionally substituted phenyl or an optionally substituted heteroarylselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl;

R³ is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R³ and R⁴ are independently C₁-C₆alkyl substituted by halogen,optionally substituted phenyl or an optionally substituted heteroarylselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl;

R² is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R², R³ and R⁴ are independently C₁-C₆alkyl substituted by halogen,optionally substituted phenyl or an optionally substituted heteroarylselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl;

R¹ is 2-methylpropyl or 2,2-dimethylpropyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuryl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuryl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R³ are —CH₂CF(CH₃)₂; and

R⁴ is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R² and R⁴ are —CH₂CF(CH₃)₂; and

R³ is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C1-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R³ and R⁴ are —CH₂CF(CH₃)₂; and

R² is 2-methylpropyl or 2,2-dimethylpropyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C1-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R², R³ and R⁴ are —CH₂CF(CH₃)₂; and

R¹ is 2-methylpropyl or 2,2-dimethylpropyl.

In another embodiment, the invention provides compounds of formula (I)wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl, C₁-C₃haloalkyl, SF₅,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,phenyl, C₃-C₆cycloalkyl, C₄-C₇heterocyclyl, C₅-C₆heteroaryl,—O—C₅-C₆heteroaryl, —S—C₅-C₆heteroaryl, —O—C₄-C₇heterocyclyl or—S—C₄-C₇heterocyclyl, wherein each cycloalkyl, heterocyclyl, phenyl orheteroaryl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen, alkoxy,haloalkoxy, alkylthio, haloalkylthio, amino, alkylamino, dialkylamino,C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl;

R¹, R², R³ and R⁴ are independently C₁-C₆alkyl substituted by halogen,optionally substituted phenyl or an optionally substituted heteroarylselected from the group consisting of thienyl, oxazolyl, isothiazolyl,1,3-4-thiadazolyl, pyrazolyl, furyl, imidazolyl, pyrrolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl; and

R⁵ and R⁶ are independently hydrogen, C₁-C₃alkyl or C₁-C₃haloalkyl.

In yet another embodiment, the invention provides compounds of formula(I) wherein:

Cy¹ and Cy² are independently phenyl or pyridyl substituted with one ormore substituents selected from the group consisting of halogen, NO₂,SF₅, methyl, CF₃, OCF₃, cyclohexyl, morpholinyl, tetrahydropyranyl,tetrahydrofuranyl, piperidinyl or pyrrolidinyl, wherein each cyclohexyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl orpyrrolidinyl is optionally further independently substituted with one ormore substituents selected from the group consisting of halogen,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, amino,C₁-C₃alkylamino, C₁-C₃dialkylamino, C₁-C₃alkyl or C₁-C₃haloalkyl;

R^(a) and R^(b) may independently be hydrogen, methyl or CF₃;

R′, R″, R″′ and R″″ are each independently hydrogen or methyl; and

R¹, R², R³ and R⁴ are each —CH₂CF(CH₃)₂.

In one embodiment, the invention provides compounds of formula (I) shownin Tables 7 to 44 below, wherein R′, R″, R″′ and R″″ are eachindependently hydrogen or C₁-C₃alkyl; and Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Tables 7 to 44 below. In the tables, Meindicates methyl.

TABLE 7 Compounds of formula (I), wherein Cy¹ and Cy² are unsubstitutedphenyl and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b)R¹ R² R³ R⁴ 7-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 7-2 CH₃ CH₂—tBuCH₂—iPr CH₂—iPr CH₂—iPr 7-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 7-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 7-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu7-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 7-7 CH₃ CH₂—tBu CH₂—iPr CH₂—tBuCH₂—iPr 7-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 7-9 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—tBu 7-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 7-11 CH₃CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 7-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu7-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 7-14 CH₃ CH₂CMe₂F CH₂—iPrCH₂—iPr CH₂—iPr 7-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 7-16 CH₃CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 7-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂CMe₂F 7-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 7-19 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂CMe₂F 7-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr7-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 7-22 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 7-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 7-24 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 7-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂FCH₂—iPr 7-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 7-27 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 7-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 7-29CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 7-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂—iPr 7-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 7-32 CH₃ CH₂CMe₂FCH₂—tBu CH₂CMe₂F CH₂—tBu 7-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 7-34CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 7-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPrCH₂CH(CF₃)₂ CH₂—iPr 7-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 7-37 HCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 7-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 7-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 7-40 H CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 7-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 7-42 H CH₂CMe₂FCH₂—tBu CH₂CMe₂F CH₂—tBu 7-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 7-44 CH₃CH₂CMe₂F nPr CH₂CMe₂F nPr 7-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 7-46 CH₃CH₂CMe₂F tBu CH₂CMe₂F tBu 7-47 CH₃ CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂FCH₂-p-biphenyl 7-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 7-49CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 7-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 7-51 CH₃CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 7-52 CH₃ CH₂CMe₂F CH₂CH₂—iPrCH₂CMe₂F CH₂CH₂—iPr 7-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr7-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 7-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 7-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 7-57CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 8 Compounds of formula (I), wherein Cy¹ and Cy² are p-fluorophenyland R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 8-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 8-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 8-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 8-4 CH₃ CH₂—iPrCH₂—iPr CH₂—tBu CH₂—iPr 8-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 8-6 CH₃CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 8-7 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr8-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 8-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPrCH₂—tBu 8-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 8-11 CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—tBu 8-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 8-13CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 8-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂—iPr 8-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 8-16 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂—iPr 8-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 8-18CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 8-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂CMe₂F 8-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 8-21 CH₃ CH₂CMe₂FCH₂—iPr CH₂—iPr CH₂CMe₂F 8-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F8-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 8-24 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂—iPr CH₂CMe₂F 8-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 8-26 CH₃CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 8-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 8-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 8-29 CH₃ CH₂—iPrCH₂—iPr CH₂—tBu CH₂—tBu 8-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 8-31CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 8-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 8-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 8-34 CH₃ CH₂CF₃CH₂—iPr CH₂CF₃ CH₂—iPr 8-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr8-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 8-37 H CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 8-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 8-39 CH₂FCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 8-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr8-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 8-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 8-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 8-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 8-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 8-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 8-47 CH₃ CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl8-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 8-49 CH₃ CH₂CMe₂F CH₃CH₂CMe₂F CH₃ 8-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 8-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 8-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 8-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 8-54 CH₃CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 8-55 CH₃ CH₂CMeF₂ CH₂—iPrCH₂CMeF₂ CH₂—iPr 8-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 8-57 CH₃CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 9 Compounds of formula (I), wherein Cy¹ and Cy² arep-trifluoromethylphenyl and R^(a), R^(b), R¹ to R⁴ are as shown in Table2. Compound # R^(a)/R^(b) R¹ R² R³ R⁴ 9-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—tBu 9-2 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 9-3 CH₃ CH₂—iPr CH₂—tBuCH₂—iPr CH₂—iPr 9-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 9-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 9-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 9-7 CH₃CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 9-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr9-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 9-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 9-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 9-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 9-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 9-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 9-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 9-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 9-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 9-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 9-19CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 9-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂FCH₂—iPr 9-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 9-22 CH₃ CH₂—iPrCH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 9-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F9-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 9-25 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂—iPr 9-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 9-27 CH₃CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 9-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr9-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 9-30 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂—iPr CH₂—iPr 9-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 9-32 CH₃CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 9-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂MeCH₂—iPr 9-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 9-35 CH₃ CH₂CH(CF₃)₂CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 9-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr9-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 9-38 Et CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 9-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 9-40 HCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 9-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr9-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 9-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂FiPr 9-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 9-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂FsBu 9-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 9-47 CH₃ CH₂CMe₂F CH₂-p-biphenylCH₂CMe₂F CH₂-p-biphenyl 9-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂FCH₂-p-tBuPh 9-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 9-50 H CH₂CMe₂F iPrCH₂CMe₂F iPr 9-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 9-52 CH₃CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 9-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 9-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 9-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 9-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 9-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 10 Compounds of formula (I), wherein Cy¹ and Cy² arep-trifluoromethoxyphenyl and R^(a), R^(b), R¹ to R⁴ are as shown.Compound # R^(a)/R^(b) R¹ R² R³ R⁴ 10-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—tBu 10-2 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 10-3 CH₃ CH₂—iPrCH₂—tBu CH₂—iPr CH₂—iPr 10-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 10-5CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 10-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—tBu 10-7 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 10-8 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—iPr 10-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 10-10CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 10-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBuCH₂—tBu 10-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 10-13 CH₃ CH₂—tBuCH₂—tBu CH₂—tBu CH₂—iPr 10-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 10-15CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 10-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂—iPr 10-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 10-18 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂—iPr 10-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F10-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 10-21 CH₃ CH₂CMe₂F CH₂—iPrCH₂—iPr CH₂CMe₂F 10-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 10-23 CH₃CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 10-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F 10-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 10-26 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 10-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr10-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 10-29 CH₃ CH₂—iPr CH₂—iPrCH₂—tBu CH₂—tBu 10-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 10-31 CH₃CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 10-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 10-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 10-34 CH₃ CH₂CF₃CH₂—iPr CH₂CF₃ CH₂—iPr 10-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr10-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 10-37 H CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 10-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 10-39 CH₂FCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 10-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr10-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 10-42 H CH₂CMe₂F CH₂—tBuCH₂CMe₂F CH₂—tBu 10-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 10-44 CH₃ CH₂CMe₂FnPr CH₂CMe₂F nPr 10-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 10-46 CH₃ CH₂CMe₂FtBu CH₂CMe₂F tBu 10-47 CH₃ CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂FCH₂-p-biphenyl 10-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 10-49CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 10-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 10-51CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 10-52 CH₃ CH₂CMe₂FCH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 10-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 10-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 10-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 10-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 10-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 11 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. # R^(a)/R^(b) R¹ R² R³ R⁴ 11-1 CH₃CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 11-2 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr11-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 11-4 CH₃ CH₂—iPr CH₂—iPrCH₂—tBu CH₂—iPr 11-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 11-6 CH₃CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 11-7 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr11-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 11-9 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—tBu 11-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 11-11 CH₃CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 11-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPrCH₂—tBu 11-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 11-14 CH₃ CH₂CMe₂FCH₂—iPr CH₂—iPr CH₂—iPr 11-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 11-16CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 11-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂CMe₂F 11-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 11-19 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂CMe₂F 11-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr11-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 11-22 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 11-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 11-24 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 11-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂FCH₂—iPr 11-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 11-27 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 11-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 11-29CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 11-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂—iPr 11-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 11-32 CH₃ CH₂CMe₂FCH₂—tBu CH₂CMe₂F CH₂—tBu 11-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr11-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 11-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPrCH₂CH(CF₃)₂ CH₂—iPr 11-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 11-37 HCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 11-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 11-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 11-40 H CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 11-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 11-42 HCH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 11-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr11-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 11-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu11-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 11-47 CH₃ CH₂CMe₂F CH₂-p-biphenylCH₂CMe₂F CH₂-p-biphenyl 11-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂FCH₂-p-tBuPh 11-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 11-50 H CH₂CMe₂F iPrCH₂CMe₂F iPr 11-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 11-52 CH₃CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 11-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 11-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 11-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 11-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 11-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 12 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴12-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 12-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 12-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 12-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 12-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu12-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 12-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 12-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 12-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 12-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 12-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 12-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 12-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 12-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 12-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 12-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 12-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 12-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr12-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 12-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 12-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 12-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 12-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 12-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 12-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 12-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F12-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 12-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 12-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 12-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 12-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 12-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 12-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 12-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 12-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 12-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 12-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 12-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 12-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 12-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 12-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 12-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 12-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 12-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 12-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 12-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 12-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 12-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 12-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃12-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 12-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 12-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 12-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 12-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 12-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 12-56 CH₃ CH₂CMeF₂ CH₂-tBu CH₂CMeF₂ CH₂—tBu 12-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 13 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴13-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 13-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 13-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 13-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 13-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu13-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 13-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 13-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 13-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 13-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 13-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 13-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 13-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 13-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 13-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 13-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 13-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 13-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr13-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 13-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 13-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 13-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 13-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 13-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 13-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 13-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F13-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 13-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 13-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 13-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 13-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 13-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 13-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 13-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 13-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 13-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 13-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 13-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 13-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 13-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 13-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 13-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 13-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 13-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 13-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 13-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 13-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 13-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 13-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃13-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 13-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 13-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 13-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 13-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 13-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 13-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 13-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 14 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴14-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 14-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 14-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 14-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 14-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu14-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 14-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 14-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 14-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 14-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 14-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 14-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 14-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 14-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 14-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 14-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 14-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 14-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr14-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 14-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 14-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 14-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 14-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 14-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 14-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 14-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F14-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 14-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 14-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 14-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 14-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 14-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 14-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 14-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 14-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 14-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 14-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 14-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 14-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 14-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 14-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 14-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 14-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 14-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 14-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 14-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 14-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 14-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 14-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃14-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 14-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 14-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 14-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 14-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 14-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 14-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 14-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 15 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴15-2 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 15-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 15-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 15-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 15-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu15-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 15-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 15-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 15-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 15-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 15-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 15-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 15-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 15-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 15-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 15-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 15-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 15-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr15-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 15-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 15-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 15-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 15-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 15-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 15-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 15-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F15-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 15-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 15-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 15-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 15-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 15-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 15-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 15-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 15-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 15-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 15-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 15-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 15-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 15-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 15-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 15-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 15-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 15-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 15-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 15-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 15-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 15-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 15-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃15-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 15-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 15-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 15-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 15-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 15-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 15-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 15-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 16 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴16-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 16-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 16-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 16-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 16-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu16-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 16-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 16-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 16-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 16-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 16-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 16-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 16-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 16-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 16-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 16-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 16-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 16-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr16-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 16-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 16-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 16-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 16-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 16-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 16-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 16-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F16-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 16-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 16-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 16-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 16-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 16-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 16-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 16-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 16-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 16-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 16-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 16-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 16-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 16-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 16-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 16-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 16-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 16-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 16-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 16-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 16-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 16-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 16-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃16-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 16-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 16-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 16-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 16-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 16-55 CH₃ CH₂CMeF ₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 16-56 CH₃ CH₂CMeF ₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 16-57 CH₃ CH₂CMeF ₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 17 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴17-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 17-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 17-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 17-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 17-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu17-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 17-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 17-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 17-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 17-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 17-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 17-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 17-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 17-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 17-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 17-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 17-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 17-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr17-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 17-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 17-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 17-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 17-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 17-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 17-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 17-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F17-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 17-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 17-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 17-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 17-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 17-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 17-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 17-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 17-35CH₃ CH₂CH(CF3)₂ CH₂—iPr CH₂CH(CF3)₂ CH₂—iPr 17-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 17-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 17-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 17-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 17-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 17-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 17-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 17-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 17-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 17-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 17-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 17-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 17-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 17-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃17-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 17-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 17-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 17-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 17-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 17-55 CH₃ CH₂CMeF ₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 17-56 CH₃ CH₂CMeF ₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 17-57 CH₃ CH₂CMeF ₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 18 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴18-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 18-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 18-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 18-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 18-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu18-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 18-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 18-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 18-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 18-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 18-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 18-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 18-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 18-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 18-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 18-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 18-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 18-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr18-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 18-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 18-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 18-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 18-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 18-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 18-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 18-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F18-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 18-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 18-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 18-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 18-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 18-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 18-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 18-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 18-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 18-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 18-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 18-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 18-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 18-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 18-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 18-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 18-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 18-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 18-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 18-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 18-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 18-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 18-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃18-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 18-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 18-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 18-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 18-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 18-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 18-56 CH₃ CH₂CMeF₂ CH₂-tBu CH₂CMeF₂ CH₂—tBu 18-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 19 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴19-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 19-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 19-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 19-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 19-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu19-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 19-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 19-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 19-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 19-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 19-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 19-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 19-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 19-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 19-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 19-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 19-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 19-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr19-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 19-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 19-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 19-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 19-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 19-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 19-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 19-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F19-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 19-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 19-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 19-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 19-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 19-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 19-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 19-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 19-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 19-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 19-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 19-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 19-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 19-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 19-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 19-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 19-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 19-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 19-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 19-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 19-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 19-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 19-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃19-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 19-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 19-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 19-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 19-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 19-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 19-56 CH₃ CH₂CMeF₂ CH₂-tBu CH₂CMeF₂ CH₂—tBu 19-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 20 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴20-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 20-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 20-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 20-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 20-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu20-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 20-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 20-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 20-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 20-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 20-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 20-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 20-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 20-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 20-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 20-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 20-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 20-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr20-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 20-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 20-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 20-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 20-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 20-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 20-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 20-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F20-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 20-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 20-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 20-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 20-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 20-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 20-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 20-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 20-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 20-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 20-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 20-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 20-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 20-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 20-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 20-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 20-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 20-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 20-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 20-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 20-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 20-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 20-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃20-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 20-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 20-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 20-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 20-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 20-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 20-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 20-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 21 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 21-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 21-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 21-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 21-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 21-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 21-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 21-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 21-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 21-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 21-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 21-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 21-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 21-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 21-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 21-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 21-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 21-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 21-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr21-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 21-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 21-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 21-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 21-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 21-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 21-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 21-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F21-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 21-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 21-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 21-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 21-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 21-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 21-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 21-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 21-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 21-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 21-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 21-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 21-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 21-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 21-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 21-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 21-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 21-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 21-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 21-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 21-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 21-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 21-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃21-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 21-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 21-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 21-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 21-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 21-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 21-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 21-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 22 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 22-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 22-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 22-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 22-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 22-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 22-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 22-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 22-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 22-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 22-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 22-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 22-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 22-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 22-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 22-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 22-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 22-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 22-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr22-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 22-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 22-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 22-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 22-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 22-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 22-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 22-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F22-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 22-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 22-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 22-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 22-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 22-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 22-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 22-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 22-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 22-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 22-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 22-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 22-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 22-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 22-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 22-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 22-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 22-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 22-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 22-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 22-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 22-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 22-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃22-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 22-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 22-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 22-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 22-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 22-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 22-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 22-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 23 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 23-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 23-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 23-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 23-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 23-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 23-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 23-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 23-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 23-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 23-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 23-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 23-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 23-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 23-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 23-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 23-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 23-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 23-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr23-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 23-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 23-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 23-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 23-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 23-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 23-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 23-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F23-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 23-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 23-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 23-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 23-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 23-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 23-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 23-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 23-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 23-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 23-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 23-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 23-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 23-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 23-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 23-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 23-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 23-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 23-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 23-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 23-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 23-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 23-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃23-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 23-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 23-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 23-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 23-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 23-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 23-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 23-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH2CMeF₂ CH₂CH₂—iPr

TABLE 24 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 24-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 24-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 24-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 24-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 24-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 24-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 24-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 24-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 24-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 24-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 24-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 24-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 24-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 24-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 24-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 24-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 24-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 24-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr24-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 24-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 24-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 24-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 24-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 24-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 24-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 24-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F24-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 24-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 24-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 24-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 24-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 24-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 24-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 24-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 24-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 24-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 24-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 24-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 24-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 24-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 24-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 24-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 24-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 24-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 24-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 24-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 24-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 24-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 24-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃24-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 24-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 24-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 24-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 24-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 24-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 24-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 24-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 25 Compounds of formula (I), wherein Cy¹ and Cy² are3,4,5-trifluorophenyl; and R^(a), R^(b), R¹ to R⁴ are as shown. Compound# R^(a)/R^(b) R¹ R² R³ R⁴ 25-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 25-2CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 25-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—iPr 25-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 25-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 25-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 25-7CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 25-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—iPr 25-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 25-10 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—tBu 25-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 25-12CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 25-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—iPr 25-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 25-15 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂—iPr 25-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr25-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 25-18 CH₃ CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 25-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 25-20 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 25-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂CMe₂F 25-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 25-23 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂CMe₂F 25-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F25-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 25-26 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 25-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 25-28 CH₃CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 25-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—tBu 25-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 25-31 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂CMe₂F 25-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu25-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 25-34 CH₃ CH₂CF₃ CH₂—iPrCH₂CF₃ CH₂—iPr 25-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 25-36CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 25-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 25-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 25-39 CH₂F CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 25-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 25-41 EtCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 25-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 25-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 25-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 25-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 25-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 25-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl25-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 25-49 CH₃ CH₂CMe₂FCH₃ CH₂CMe₂F CH₃ 25-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 25-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 25-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 25-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 25-54CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 25-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 25-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu25-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 26 Compounds of formula (I), wherein Cy¹ and Cy² arep-aminophenyl; and R^(a), R^(b), R¹ to R⁴ are as shown. Compound #R^(a)/R^(b) R¹ R² R³ R⁴ 26-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 26-2CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 26-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—iPr 26-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 26-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 26-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 26-7CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 26-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—iPr 26-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 26-10 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—tBu 26-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 26-12CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 26-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—iPr 26-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 26-15 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂—iPr 26-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr26-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 26-18 CH₃ CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 26-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 26-20 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 26-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂CMe₂F 26-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 26-23 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂CMe₂F 26-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F26-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 26-26 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 26-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 26-28 CH₃CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 26-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—tBu 26-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 26-31 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂CMe₂F 26-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu26-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 26-34 CH₃ CH₂CF₃ CH₂—iPrCH₂CF₃ CH₂—iPr 26-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 26-36CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 26-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 26-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 26-39 CH₂F CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 26-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 26-41 EtCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 26-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 26-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 26-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 26-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 26-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 26-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl26-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 26-49 CH₃ CH₂CMe₂FCH₃ CH₂CMe₂F CH₃ 26-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 26-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 26-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 26-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 26-54CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 26-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 26-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu26-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 27 Compounds of formula (I), wherein Cy¹ and Cy² are p-iodophenyl;and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 27-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 27-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 27-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 27-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 27-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu27-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 27-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 27-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 27-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 27-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 27-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 27-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 27-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 27-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 27-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 27-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 27-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 27-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr27-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 27-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 27-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 27-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 27-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 27-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 27-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 27-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F27-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 27-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 27-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 27-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 27-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 27-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 27-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 27-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 27-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 27-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 27-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 27-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 27-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 27-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 27-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 27-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 27-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 27-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 27-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 27-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 27-47 CH₃CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl 27-48 CH₃ CH₂CMe₂FCH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 27-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃27-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 27-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 27-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 27-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂—p-pyridyl CH₂—iPr 27-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂—p-pyridyl CH₂—tBu 27-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 27-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 27-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 28 Compounds of formula (I), wherein Cy¹ and Cy² arep-bromophenyl; and R^(a), R^(b), R¹ to R⁴ are as shown. Compound #R^(a)/R^(b) R¹ R² R³ R⁴ 28-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 28-2CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 28-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—iPr 28-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 28-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 28-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 28-7CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 28-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—iPr 28-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 28-10 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—tBu 28-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 28-12CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 28-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—iPr 28-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 28-15 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂—iPr 28-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr28-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 28-18 CH₃ CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 28-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 28-20 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 28-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂CMe₂F 28-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 28-23 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂CMe₂F 28-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F28-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 28-26 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 28-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 28-28 CH₃CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 28-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—tBu 28-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 28-31 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂CMe₂F 28-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu28-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 28-34 CH₃ CH₂CF₃ CH₂—iPrCH₂CF₃ CH₂—iPr 28-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 28-36CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 28-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 28-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 28-39 CH₂F CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 28-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 28-41 EtCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 28-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 28-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 28-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 28-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 28-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 28-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl28-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 28-49 CH₃ CH₂CMe₂FCH₃ CH₂CMe₂F CH₃ 28-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 28-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 28-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 28-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 28-54CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 28-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 28-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu28-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 29 Compounds of formula (I), wherein Cy¹ and Cy² arep-cyanophenyl; and R^(a), R^(b), R¹ to R⁴ are as shown. Compound #R^(a)/R^(b) R¹ R² R³ R⁴ 29-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 29-2CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 29-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—iPr 29-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 29-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 29-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 29-7CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 29-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—iPr 29-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 29-10 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—tBu 29-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 29-12CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 29-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—iPr 29-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 29-15 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂—iPr 29-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr29-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 29-18 CH₃ CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 29-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 29-20 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 29-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂CMe₂F 29-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 29-23 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂CMe₂F 29-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F29-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 29-26 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 29-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 29-28 CH₃CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 29-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—tBu 29-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 29-31 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂CMe₂F 29-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu29-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 29-34 CH₃ CH₂CF₃ CH₂—iPrCH₂CF₃ CH₂—iPr 29-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 29-36CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 29-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 29-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 29-39 CH₂F CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 29-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 29-41 EtCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 29-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 29-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 29-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 29-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 29-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 29-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl29-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 29-49 CH₃ CH₂CMe₂FCH₃ CH₂CMe₂F CH₃ 29-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 29-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 29-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 29-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 29-54CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 29-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 29-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu29-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 30 Compounds of formula (I), wherein Cy¹ and Cy² are

and unsubstituted phenyl, respectively; and R^(a), R^(b), R¹ to R⁴ areas shown. R^(a), R^(b), # R^(a)/R^(b) R¹ R² R³ R⁴ 30-1  CH₃ CH₂—tBuCH₂—tBu CH₂—tBu CH₂—tBu 30-2  CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 30-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 30-4  CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—iPr 30-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 30-6  CH₃ CH₂—iPrCH₂—tBu CH₂—iPr CH₂—tBu 30-7  CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 30-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 30-9  CH₃ CH₂—tBu CH₂—iPr CH₂—iPrCH₂—tBu 30-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 30-11 CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—tBu 30-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 30-13CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 30-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂—iPr 30-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 30-16 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂—iPr 30-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F30-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 30-19 CH₃ CH₂—iPr CH₂CMe₂FCH₂—iPr CH₂CMe₂F 30-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 30-21 CH₃CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 30-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F 30-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 30-24 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂—iPr CH₂CMe₂F 30-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr30-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 30-27 CH₃ CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 30-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 30-29 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 30-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂—iPr 30-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 30-32 CH₃ CH₂CMe₂FCH₂—tBu CH₂CMe₂F CH₂—tBu 30-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr30-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 30-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPrCH₂CH(CF₃)₂ CH₂—iPr 30-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 30-37 HCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 30-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 30-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 30-40 H CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 30-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 30-42 HCH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 30-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr30-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 30-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu30-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 30-47 CH₃ CH₂CMe₂F CH₂-p-biphenylCH₂CMe₂F CH₂-p-biphenyl 30-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂FCH₂-p-tBuPh 30-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 30-50 H CH₂CMe₂F iPrCH₂CMe₂F iPr 30-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 30-52 CH₃CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 30-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 30-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 30-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 30-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 30-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 31 Compounds of formula (I), wherein Cy¹ and Cy² are

and p-iodophenyl, respectively; and R^(a), R^(b), R¹ to R⁴ are as shown.Compound # R^(a)/R^(b) R¹ R² R³ R⁴ 31-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—tBu 31-2  CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 31-3  CH₃ CH₂—iPrCH₂—tBu CH₂—iPr CH₂—iPr 31-4  CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 31-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 31-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—tBu 31-7  CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 31-8  CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—iPr 31-9  CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 31-10CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 31-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBuCH₂—tBu 31-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 31-13 CH₃ CH₂—tBuCH₂—tBu CH₂—tBu CH₂—iPr 31-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 31-15CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 31-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂—iPr 31-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 31-18 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂—iPr 31-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F31-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 31-21 CH₃ CH₂CMe₂F CH₂—iPrCH₂—iPr CH₂CMe₂F 31-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 31-23 CH₃CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 31-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F 31-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 31-26 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 31-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr31-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 31-29 CH₃ CH₂—iPr CH₂—iPrCH₂—tBu CH₂—tBu 31-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 31-31 CH₃CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 31-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 31-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 31-34 CH₃ CH₂CF₃CH₂—iPr CH₂CF₃ CH₂—iPr 31-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr31-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 31-37 H CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 31-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 31-39 CH₂FCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 31-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr31-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 31-42 H CH₂CMe₂F CH₂—tBuCH₂CMe₂F CH₂—tBu 31-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 31-44 CH₃ CH₂CMe₂FnPr CH₂CMe₂F nPr 31-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 31-46 CH₃ CH₂CMe₂FtBu CH₂CMe₂F tBu 31-47 CH₃ CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂FCH₂-p-biphenyl 31-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 31-49CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 31-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 31-51CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 31-52 CH₃ CH₂CMe₂FCH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 31-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 31-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 31-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 31-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 31-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 32 Compounds of formula (I), wherein Cy¹ and Cy² are

and unsubstituted phenyl, respectively; and R^(a), R^(b), R¹ to R⁴ areas shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴ 32-1  CH₃ CH₂—tBu CH₂—tBuCH₂—tBu CH₂—tBu 32-2  CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 32-3  CH₃CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 32-4  CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—iPr 32-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 32-6  CH₃ CH₂—iPrCH₂—tBu CH₂—iPr CH₂—tBu 32-7  CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 32-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 32-9  CH₃ CH₂—tBu CH₂—iPr CH₂—iPrCH₂—tBu 32-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 32-11 CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—tBu 32-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 32-13CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 32-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂—iPr 32-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 32-16 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂—iPr 32-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F32-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 32-19 CH₃ CH₂—iPr CH₂CMe₂FCH₂—iPr CH₂CMe₂F 32-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 32-21 CH₃CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 32-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F 32-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 32-24 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂—iPr CH₂CMe₂F 32-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr32-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 32-27 CH₃ CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 32-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 32-29 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 32-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂—iPr 32-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 32-32 CH₃ CH₂CMe₂FCH₂—tBu CH₂CMe₂F CH₂—tBu 32-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr32-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 32-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPrCH₂CH(CF₃)₂ CH₂—iPr 32-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 32-37 HCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 32-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 32-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 32-40 H CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 32-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 32-42 HCH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 32-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr32-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 32-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu32-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 32-47 CH₃ CH₂CMe₂F CH₂-p-biphenylCH₂CMe₂F CH₂-p-biphenyl 32-48 CH₃ CH₂CMe₂F CH₂-p-tBuPh CH₂CMe₂FCH₂-p-tBuPh 32-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 32-50 H CH₂CMe₂F iPrCH₂CMe₂F iPr 32-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 32-52 CH₃CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 32-53 CH₃ CH₂-p-pyridyl CH₂—iPrCH₂-p-pyridyl CH₂—iPr 32-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridylCH₂—tBu 32-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 32-56 CH₃ CH₂CMeF₂CH₂—tBu CH₂CMeF₂ CH₂—tBu 32-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂CH₂CH₂—iPr

TABLE 33 Compounds of formula (I), wherein Cy¹ and Cy² arep-nitrophenyl; and R^(a) , R^(b), R¹ to R⁴ are as shown. Compound #R^(a)/R^(b) R¹ R² R³ R⁴ 33-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 33-2CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 33-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—iPr 33-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 33-5 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂—tBu 33-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 33-7CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 33-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—iPr 33-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 33-10 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—tBu 33-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 33-12CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 33-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—iPr 33-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 33-15 CH₃ CH₂—iPrCH₂CMe₂F CH₂—iPr CH₂—iPr 33-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr33-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 33-18 CH₃ CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 33-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 33-20 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 33-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPrCH₂CMe₂F 33-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 33-23 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂CMe₂F 33-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F33-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 33-26 CH₃ CH₂CMe₂F CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F 33-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 33-28 CH₃CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 33-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBuCH₂—tBu 33-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 33-31 CH₃ CH₂—iPrCH₂—iPr CH₂CMe₂F CH₂CMe₂F 33-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu33-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 33-34 CH₃ CH₂CF₃ CH₂—iPrCH₂CF₃ CH₂—iPr 33-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 33-36CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 33-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂—iPr 33-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 33-39 CH₂F CH₂—iPrCH₂—iPr CH₂—iPr CH₂—iPr 33-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 33-41 EtCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 33-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 33-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 33-44 CH₃ CH₂CMe₂F nPrCH₂CMe₂F nPr 33-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 33-46 CH₃ CH₂CMe₂F tBuCH₂CMe₂F tBu 33-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenyl biphenyl33-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 33-49 CH₃ CH₂CMe₂FCH₃ CH₂CMe₂F CH₃ 33-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 33-51 CH₃ CH₂CMe₂FCH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 33-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂FCH₂CH₂—iPr 33-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 33-54CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 33-55 CH₃ CH₂CMeF₂CH₂—iPr CH₂CMeF₂ CH₂—iPr 33-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu33-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 34 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 34-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 34-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 34-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 34-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 34-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 34-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 34-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 34-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 34-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 34-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 34-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 34-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 34-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 34-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 34-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 34-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 34-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 34-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr34-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 34-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 34-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 34-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 34-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 34-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 34-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 34-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F34-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 34-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 34-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 34-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 34-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 34-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 34-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 34-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 34-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 34-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 34-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 34-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 34-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 34-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 34-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 34-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 34-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 34-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 34-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 34-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 34-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 34-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 34-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃34-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 34-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 34-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 34-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 34-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 34-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 34-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 34-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 35 Compounds of formula (I), wherein Cy¹ and Cy² are

and R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³R⁴ 35-1  CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 35-2  CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 35-3  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 35-4  CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 35-5  CH₃ CH₂—iPr CH₂—iPr CH₂—iPrCH₂—tBu 35-6  CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 35-7  CH₃ CH₂—tBuCH₂—iPr CH₂—tBu CH₂—iPr 35-8  CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 35-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 35-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 35-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 35-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 35-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 35-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 35-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 35-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 35-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 35-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr35-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 35-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 35-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 35-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 35-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 35-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 35-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 35-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F35-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 35-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 35-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 35-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 35-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 35-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 35-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 35-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 35-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 35-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 35-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 35-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 35-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 35-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 35-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 35-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 35-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 35-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 35-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 35-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 35-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 35-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 35-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃35-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 35-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 35-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 35-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 35-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 35-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 35-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 35-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 36 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a),R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴36-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 36-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 36-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 36-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 36-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu36-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 36-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 36-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 36-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 36-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 36-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 36-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 36-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 36-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 36-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 36-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 36-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 36-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr36-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 36-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 36-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 36-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 36-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 36-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 36-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 36-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F36-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 36-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 36-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 36-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 36-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 36-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 36-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 36-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 36-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 36-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 36-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 36-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 36-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 36-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 36-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 36-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 36-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 36-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 36-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 36-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 36-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 36-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 36-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃36-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 36-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 36-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 36-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 36-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 36-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 36-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 36-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 37 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴37-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 37-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 37-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 37-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 37-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu37-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 37-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 37-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 37-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 37-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 37-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 37-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 37-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 37-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 37-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 37-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 37-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 37-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr37-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 37-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 37-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 37-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 37-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 37-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 37-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 37-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F37-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 37-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 37-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 37-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 37-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 37-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 37-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 37-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 37-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 37-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 37-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 37-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 37-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 37-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 37-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 37-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 37-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 37-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 37-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 37-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 37-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 37-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 37-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃37-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 37-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 37-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 37-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 37-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 37-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 37-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 37-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 38 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴38-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 38-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 38-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 38-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 38-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu38-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 38-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 38-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 38-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 38-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 38-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 38-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 38-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 38-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 38-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 38-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 38-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 38-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr38-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 38-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 38-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 38-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 38-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 38-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 38-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 38-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F38-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 38-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 38-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 38-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 38-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 38-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 38-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 38-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 38-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 38-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 38-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 38-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 38-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 38-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 38-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 38-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 38-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 38-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 38-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 38-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 38-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 38-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 38-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃38-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 38-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 38-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 38-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 38-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 38-55 CH₃ CH₂CMeF₂ CH₂-iPr CH₂CMeF₂CH₂—iPr 38-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 38-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 39 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴39-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 39-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 39-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 39-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 39-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu39-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 39-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 39-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 39-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 39-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 39-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 39-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 39-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 39-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 39-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 39-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 39-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 39-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr39-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 39-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 39-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 39-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 39-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 39-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 39-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 39-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F39-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 39-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 39-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 39-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 39-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 39-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 39-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 39-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 39-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 39-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 39-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 39-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 39-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 39-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 39-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 39-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 39-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 39-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 39-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 39-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 39-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 39-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 39-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃39-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 39-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 39-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 39-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 39-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 39-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 39-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 39-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 40 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴40-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 40-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 40-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 40-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 40-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu40-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 40-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 40-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 40-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 40-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 40-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 40-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 40-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 40-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 40-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 40-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 40-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 40-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr40-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 40-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 40-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 40-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 40-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 40-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 40-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 40-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F40-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 40-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 40-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 40-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 40-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 40-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 40-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 40-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 40-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 40-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 40-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 40-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 40-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 40-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 40-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 40-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 40-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 40-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 40-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 40-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 40-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 40-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 40-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃40-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 40-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 40-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 40-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 40-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 40-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 40-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 40-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 41 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴41-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 41-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 41-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 41-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 41-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu41-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 41-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 41-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 41-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 41-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 41-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 41-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 41-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 41-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 41-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 41-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 41-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 41-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr41-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 41-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 41-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 41-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 41-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 41-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 41-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 41-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F41-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 41-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 41-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 41-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 41-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 41-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 41-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 41-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 41-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 41-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 41-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 41-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 41-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 41-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 41-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 41-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 41-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 41-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 41-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 41-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 41-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 41-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 41-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃41-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 41-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 41-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 41-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 41-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 41-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 41-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 41-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 42 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴42-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 42-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 42-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 42-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 42-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu42-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 42-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 42-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 42-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 42-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 42-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 42-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 42-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 42-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 42-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 42-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 42-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 42-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr42-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 42-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 42-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 42-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 42-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 42-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 42-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 42-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F42-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 42-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 42-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 42-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 42-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 42-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 42-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 42-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 42-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 42-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 42-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 42-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 42-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 42-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 42-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 42-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 42-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 42-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 42-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 42-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 42-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 42-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 42-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃42-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 42-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 42-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 42-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 42-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 42-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 42-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 42-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 43 Compounds of formula (I), wherein Cy¹ and Cy² are

R^(a), R^(b), R¹ to R⁴ are as shown. Compound # R^(a)/R^(b) R¹ R² R³ R⁴43-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—tBu 43-2 CH₃ CH₂—tBu CH₂—iPrCH₂—iPr CH₂—iPr 43-3 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—iPr 43-4 CH₃CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 43-5 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu43-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPr CH₂—tBu 43-7 CH₃ CH₂—tBu CH₂—iPrCH₂—tBu CH₂—iPr 43-8 CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—iPr 43-9 CH₃CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 43-10 CH₃ CH₂—iPr CH₂—tBu CH₂—tBuCH₂—tBu 43-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—tBu 43-12 CH₃ CH₂—tBuCH₂—tBu CH₂—iPr CH₂—tBu 43-13 CH₃ CH₂—tBu CH₂—tBu CH₂—tBu CH₂—iPr 43-14CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 43-15 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPrCH₂—iPr 43-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂—iPr 43-17 CH₃ CH₂—iPrCH₂—iPr CH₂—iPr CH₂CMe₂F 43-18 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr43-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F 43-20 CH₃ CH₂—iPr CH₂CMe₂FCH₂CMe₂F CH₂—iPr 43-21 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂CMe₂F 43-22 CH₃CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 43-23 CH₃ CH₂CMe₂F CH₂—iPr CH₂CMe₂FCH₂CMe₂F 43-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F 43-25 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂—iPr 43-26 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F43-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 43-28 CH₃ CH₂—tBu CH₂—tBuCH₂—iPr CH₂—iPr 43-29 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—tBu 43-30 CH₃CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 43-31 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂CMe₂F 43-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 43-33 CH₃ CH₂CF₂MeCH₂—iPr CH₂CF₂Me CH₂—iPr 43-34 CH₃ CH₂CF₃ CH₂—iPr CH₂CF₃ CH₂—iPr 43-35CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr 43-36 CH₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 43-37 H CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 43-38 EtCH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 43-39 CH₂F CH₂—iPr CH₂—iPr CH₂—iPrCH₂—iPr 43-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 43-41 Et CH₂—iPr CH₂—iPrCH₂—iPr CH₂—iPr 43-42 H CH₂CMe₂F CH₂—tBu CH₂CMe₂F CH₂—tBu 43-43 CH₃CH₂CMe₂F iPr CH₂CMe₂F iPr 43-44 CH₃ CH₂CMe₂F nPr CH₂CMe₂F nPr 43-45 CH₃CH₂CMe₂F sBu CH₂CMe₂F sBu 43-46 CH₃ CH₂CMe₂F tBu CH₂CMe₂F tBu 43-47 CH₃CH₂CMe₂F CH₂-p-biphenyl CH₂CMe₂F CH₂-p-biphenyl 43-48 CH₃ CH₂CMe₂FCH₂-p-tBuPh CH₂CMe₂F CH₂-p-tBuPh 43-49 CH₃ CH₂CMe₂F CH₃ CH₂CMe₂F CH₃43-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 43-51 CH₃ CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂FCH₂CH₂CMe₃ 43-52 CH₃ CH₂CMe₂F CH₂CH₂—iPr CH₂CMe₂F CH₂CH₂—iPr 43-53 CH₃CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridyl CH₂—iPr 43-54 CH₃ CH₂-p-pyridylCH₂—tBu CH₂-p-pyridyl CH₂—tBu 43-55 CH₃ CH₂CMeF₂ CH₂—iPr CH₂CMeF₂CH₂—iPr 43-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂ CH₂—tBu 43-57 CH₃ CH₂CMeF₂CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

TABLE 44 Compounds of formula (I), wherein Cy¹ and Cy² are p-trifluoromethylthiophenyl; and R^(a), R^(b), R¹ to R⁴ are as shown.Compound # R^(a)/R^(b) R¹ R² R³ R⁴ 44-1 CH₃ CH₂—tBu CH₂—tBu CH₂—tBuCH₂—tBu 44-2 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—iPr 44-3 CH₃ CH₂—iPrCH₂—tBu CH₂—iPr CH₂—iPr 44-4 CH₃ CH₂—iPr CH₂—iPr CH₂—tBu CH₂—iPr 44-5CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—tBu 44-6 CH₃ CH₂—iPr CH₂—tBu CH₂—iPrCH₂—tBu 44-7 CH₃ CH₂—tBu CH₂—iPr CH₂—tBu CH₂—iPr 44-8 CH₃ CH₂—iPrCH₂—tBu CH₂—tBu CH₂—iPr 44-9 CH₃ CH₂—tBu CH₂—iPr CH₂—iPr CH₂—tBu 44-10CH₃ CH₂—iPr CH₂—tBu CH₂—tBu CH₂—tBu 44-11 CH₃ CH₂—tBu CH₂—iPr CH₂—tBuCH₂—tBu 44-12 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—tBu 44-13 CH₃ CH₂—tBuCH₂—tBu CH₂—tBu CH₂—iPr 44-14 CH₃ CH₂CMe₂F CH₂—iPr CH₂—iPr CH₂—iPr 44-15CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂—iPr 44-16 CH₃ CH₂—iPr CH₂—iPr CH₂CMe₂FCH₂—iPr 44-17 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂CMe₂F 44-18 CH₃ CH₂CMe₂FCH₂—iPr CH₂CMe₂F CH₂—iPr 44-19 CH₃ CH₂—iPr CH₂CMe₂F CH₂—iPr CH₂CMe₂F44-20 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂—iPr 44-21 CH₃ CH₂CMe₂F CH₂—iPrCH₂—iPr CH₂CMe₂F 44-22 CH₃ CH₂—iPr CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 44-23 CH₃CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂CMe₂F 44-24 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPrCH₂CMe₂F 44-25 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂CMe₂F CH₂—iPr 44-26 CH₃ CH₂CMe₂FCH₂CMe₂F CH₂CMe₂F CH₂CMe₂F 44-27 CH₃ CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr44-28 CH₃ CH₂—tBu CH₂—tBu CH₂—iPr CH₂—iPr 44-29 CH₃ CH₂—iPr CH₂—iPrCH₂—tBu CH₂—tBu 44-30 CH₃ CH₂CMe₂F CH₂CMe₂F CH₂—iPr CH₂—iPr 44-31 CH₃CH₂—iPr CH₂—iPr CH₂CMe₂F CH₂CMe₂F 44-32 CH₃ CH₂CMe₂F CH₂—tBu CH₂CMe₂FCH₂—tBu 44-33 CH₃ CH₂CF₂Me CH₂—iPr CH₂CF₂Me CH₂—iPr 44-34 CH₃ CH₂CF₃CH₂—iPr CH₂CF₃ CH₂—iPr 44-35 CH₃ CH₂CH(CF₃)₂ CH₂—iPr CH₂CH(CF₃)₂ CH₂—iPr44-36 CH₂F CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 44-37 H CH₂CMe₂F CH₂—iPrCH₂CMe₂F CH₂—iPr 44-38 Et CH₂CMe₂F CH₂—iPr CH₂CMe₂F CH₂—iPr 44-39 CH₂FCH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 44-40 H CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr44-41 Et CH₂—iPr CH₂—iPr CH₂—iPr CH₂—iPr 44-42 H CH₂CMe₂F CH₂—tBuCH₂CMe₂F CH₂—tBu 44-43 CH₃ CH₂CMe₂F iPr CH₂CMe₂F iPr 44-44 CH₃ CH₂CMe₂FnPr CH₂CMe₂F nPr 44-45 CH₃ CH₂CMe₂F sBu CH₂CMe₂F sBu 44-46 CH₃ CH₂CMe₂FtBu CH₂CMe₂F tBu 44-47 CH₃ CH₂CMe₂F CH₂-p- CH₂CMe₂F CH₂-p- biphenylbiphenyl 44-48 CH₃ CH₂CMe₂F CH₂—p-tBuPh CH₂CMe₂F CH₂—p-tBuPh 44-49 CH₃CH₂CMe₂F CH₃ CH₂CMe₂F CH₃ 44-50 H CH₂CMe₂F iPr CH₂CMe₂F iPr 44-51 CH₃CH₂CMe₂F CH₂CH₂CMe₃ CH₂CMe₂F CH₂CH₂CMe₃ 44-52 CH₃ CH₂CMe₂F CH₂CH₂—iPrCH₂CMe₂F CH₂CH₂—iPr 44-53 CH₃ CH₂-p-pyridyl CH₂—iPr CH₂-p-pyridylCH₂—iPr 44-54 CH₃ CH₂-p-pyridyl CH₂—tBu CH₂-p-pyridyl CH₂—tBu 44-55 CH₃CH₂CMeF₂ CH₂—iPr CH₂CMeF₂ CH₂—iPr 44-56 CH₃ CH₂CMeF₂ CH₂—tBu CH₂CMeF₂CH₂—tBu 44-57 CH₃ CH₂CMeF₂ CH₂CH₂—iPr CH₂CMeF₂ CH₂CH₂—iPr

Particular embodiments of the compounds of the invention are furtherdescribed in Tables 45-120 wherein the meaning of the variables Cy¹,Cy², R^(a), R^(b), R¹, R², R³ and R⁴ are as described for Tables 7-44,respectively, with the exception that R′, R″, R″′ and R″″ are eachspecifically defined below.

Table 45: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 7, and R′, R″, R″′ and R″″ are eachmethyl.

Table 46: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 8, and R′, R″, R″′ and R″′ are eachmethyl.

Table 47: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 9, and R′, R″, R″′ and R″″ are eachmethyl.

Table 48: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 10, and R′, R″, R″′ and R″″ are eachmethyl.

Table 49: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 11, and R′, R″, R″′ and R″″ are eachmethyl.

Table 50: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 12, and R′, R″, R″′ and R″″ are eachmethyl.

Table 51: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 13, and R′, R″, R″′ and R″″ are eachmethyl.

Table 52: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 14, and R′, R″, R″′ and R″″ are eachmethyl.

Table 53: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 15, and R′, R″, R″′ and R″″ are eachmethyl.

Table 54: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 16, and R′, R″, R″′ and R″″ are eachmethyl.

Table 55: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 17, and R′, R″, R″′ and R″″ are eachmethyl.

Table 56: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 18, and R′, R″, R″′ and R″″ are eachmethyl.

Table 57: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 19, and R′, R″, R″′ and R″″ are eachmethyl.

Table 58: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 20, and R′, R″, R″′ and R″″ are eachmethyl.

Table 59: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 21, and R′, R″, R″′ and R″″ are eachmethyl.

Table 60: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 22, and R′, R″, R″′ and R″″ are eachmethyl.

Table 61: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 23, and R′, R″, R″′ and R″″ are eachmethyl.

Table 62: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 24, and R′, R″, R″′ and R″″ are eachmethyl.

Table 63: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 25, and R′, R″, R″′ and R″″ are eachmethyl.

Table 64: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 26, and R′, R″, R″′ and R″″ are eachmethyl.

Table 65: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 27, and R′, R″, R″′ and R″″ are eachmethyl.

Table 66: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 28, and R′, R″, R″′ and R″″ are eachmethyl.

Table 67: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 29, and R′, R″, R″′ and R″″ are eachmethyl.

Table 68: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 30, and R′, R″, R″′ and R″″ are eachmethyl.

Table 69: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 31, and R′, R″, R″′ and R″″ are eachmethyl.

Table 70: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 32, and R′, R″, R″′ and R″″ are eachmethyl.

Table 71: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 33, and R′, R″, R″′ and R″″ are eachmethyl.

Table 72: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 34, and R′, R″, R″′ and R″″ are eachmethyl.

Table 73: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 35, and R′, R″, R″′ and R″″ are eachmethyl.

Table 74: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 36, and R′, R″, R″′ and R″″ are eachmethyl.

Table 75: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 37, and R′, R″, R″′ and R″″ are eachmethyl.

Table 76: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 38, and R′, R″, R″′ and R″″ are eachmethyl.

Table 77: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 39, and R′, R″, R″′ and R″″ are eachmethyl.

Table 78: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 40, and R′, R″, R″′ and R″″ are eachmethyl.

Table 79: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 41, and R′, R″, R″′ and R″″ are eachmethyl.

Table 80: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 42, and R′, R″, R″′ and R″″ are eachmethyl.

Table 81: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 43, and R′, R″, R″′ and R″″ are eachmethyl.

Table 82: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 44, and R′, R″, R″′ and R″″ are eachmethyl.

Table 83: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 7, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 84: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 8, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 85: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 9, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 86: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 10, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 87: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 11, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 88: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 12, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 89: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 13, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 90: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 14, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 91: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 15, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 92: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 16, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 93: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 17, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 94: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 18, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 95: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 19, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 96: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 20, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 97: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 21, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 98: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 22, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 99: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 23, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 100: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 24, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 101: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 25, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 102: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 26, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 103: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 27, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 104: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 28, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 105: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 29, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 106: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 30, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 107: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 31, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 108: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 32, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 109: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 33, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 110: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 34, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 111: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 35, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 112: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 36, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 113: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 37, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 114: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 38, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 115: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 39, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 116: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 40, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 117: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 41, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 118: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 42, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 119: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 43, and R′, R″, R″′ and R″″ are eachhydrogen.

Table 120: Compounds of formula (I), wherein Cy¹, Cy², R^(a), R^(b), R¹,R², R³ and R⁴ are as shown in Table 44, and R′, R″, R″′ and R″″ are eachhydrogen.

Surprisingly, it has been found that substitution of the alkyl groupsR¹, R², R³ and R⁴, which are 2-methylpropyl groups in the parent cyclicdepsipeptide PF1022 and also in emodepside, with certain groups improvethe in vitro metabolic stability of the compounds and may also improvethe activity of the compounds against endoparasites and ectoparasites.Furthermore, it has been surprisingly found that substitution of thecompounds of formula (I) with certain Cy¹ and/or Cy² groups alsosignificantly improves the in vitro metabolic stability of the compoundsof the invention compared with PF1022 and emodepside. In embodiments,the compounds of formula (I) with certain substituents will also exhibitimproved activity against ectoparasites.

It has also been surprisingly found that the spatial order ofsubstitution of R¹ to R⁴ also has a significant impact on the activityof the compounds. For example it has been found that when thenaturally-occurring 2-methylpropyl groups of PF1022A and emodepsiderepresented by positions identified as R¹ and R³ in the compound offormula (I) are modified the activity of the compounds is significantlyimproved over compounds where the 2-methylpropyl groups at the positionsR² and R⁴ are substituted. Thus, it is even more surprising that thecyclic depsipeptides having non-natural stereochemical configurations atone or more of the carbon atoms bearing the groups Cy¹, Cy², R^(a),R^(b), R¹, R², R³ and R⁴ retain the potent activity against parasites.The compounds of the invention where the groups Cy¹ and/or Cy² and atleast one of R¹, R², R³ and R⁴ are substituted with certain substituentsand wherein at least one of the carbon atoms bearing the groups Cy¹,Cy², R^(a), R^(b), R¹, R², R³ and R⁴ have a stereochemical configurationthat is inverted compared with the corresponding carbon atom in PF1022Ahave been found to have significantly improved metabolic stability andequal or improved efficacy against endoparasites including Dirofilariaimmitis microfilaria and/or L3 and L4 larvae and/or Haemonchus contortuslarvae.

The influence of certain substituents on one or more of R¹, R², R³ andR⁴ is also surprising. Thus, substitution of one or more of R¹, R², R³and R⁴ with fluoro has been found to significantly improve the in vitroactivity of the compounds of formula (I) on the motility of Haemonchuscontortus larvae and Dirofilaria immitis microfilaria compared withunsubstituted compounds (e.g. PF1022 or analogs where Cy¹ and/or Cy² aresubstituted phenyl but R¹ to R⁴ are 2-methylpropyl) or compounds inwhich the naturally-occurring 2-methylpropyl groups of PF1022A andemodepside, represented by positions identified as R¹ and R³ in thecompound of formula (I), are substituted with a methyl group. Inaddition, the substitution of R¹ and R³ groups with fluoro has beenfound to result in significantly improved in vitro activity against H.contortus larvae and D. immitis microfilaria compared with compoundssubstituted with fluoro at R² or other combinations. It is apparent thatthe type of substitution in groups R¹, R², R³ and R⁴ as well as which ofR¹, R², R³ and R⁴ are substituted have a significant influence on theactivity of the compounds.

Scherkenbeck et al. (Bioorg. Med. Chem. Lett. 8 (1998), 1035-1040)described that the replacement of the N-methyl leucine residues for aseries of related N-methylated amino acids such as isoleucine, valine,norvaline, alanine and phenylalanine resulted in nearly complete loss ofanthelmintic efficacy following oral administration in sheep.Furthermore, the publication reported that modification of half of theN-methyl leucine residues with either methyl or n-propyl side chainsalso surprisingly resulted in significantly reduced activity. It wasconcluded that the (L)-N-methyl leucine residues in the cyclicdepsipeptide PF1022A were a critical part of the pharmacophore andessential for in vivo activity.

Thus, it is surprising and unexpected that modification of the groups R¹to R⁴ in the compound of formula (I), which correspond to the N-methylleucine residues in PF1022A or emodepside, result in enhanced in vitrometabolic stability and/or improved activity compared with the compoundscontaining unmodified N-methyl leucine residues. It is also verysurprising and unexpected that the compounds of formula (I) in which thealkyl groups represented by R¹ and R³ are substituted with certaingroups exhibit significantly improved efficacy against endoparasitescompared to compounds that are substituted with the same groups at R²and R⁴ or in other combinations. In addition, the inclusion of certainsubstituents in groups R¹ to R⁴ and Cy¹ and Cy² result in improved invitro metabolic stability compared with unsubstituted compounds. Itfollows that an appropriate combination of the substitution at Cy¹ andCy² and R¹ to R⁴ in the compounds of formula (I) results insignificantly improved activity against endoparasites and improvedmetabolic stability in animals.

Furthermore, the substitution of the naturally-occurring 2-methylpropylgroups of PF1022A and emodepside, represented by positions R¹ and R³ inthe compound of formula (I), with certain substituents, including fluoroand methyl, has been found to improve the in vitro permeability of thecompounds. For example, compounds of formula (I) wherein Cy¹ and Cy² areeither both unsubstituted phenyl or p-fluorophenyl groups and R² and R⁴,respectively, are 2-methylpropyl fluoro-substituted were found to havesignificantly improved permeability compared with the compounds where R²and R⁴ are unsubstituted 2-methylpropyl. Further, compounds where Cy¹and Cy² are p-morpholino phenyl and R² and R⁴ are methyl-substituted2-methylpropyl were found to have significantly improved permeabilitycompared with emodepside (R² and R⁴=2-methylpropyl).

The characteristics described above for the compounds of formula (I) areexpected to result in compounds with superior antiparasitic efficacyagainst endoparasites and ectoparasites in or on animals.

Stereoisomers and Polymorphic Forms

It will be appreciated by those of skill in the art that the compoundsof the invention may exist and be isolated as optically active andracemic forms. Compounds having one or more chiral centers, includingthat at a sulfur atom, may be present as single enantiomers ordiastereomers or as mixtures of enantiomers and/or diastereomers. Forexample, it is well known in the art that sulfoxide compounds may beoptically active and may exist as single enantiomers or racemicmixtures. In addition, compounds of the invention may include one ormore chiral centers, which results in a theoretical number of opticallyactive isomers. Where compounds of the invention include n chiralcenters, the compounds may comprise up to 2^(n) optical isomers. Thepresent invention encompasses the specific enantiomers or diastereomersof each compound as well as mixtures of different enantiomers and/ordiastereomers of the compounds of the invention that possess the usefulproperties described herein. The optically active forms can be preparedby, for example, resolution of the racemic forms by selectivecrystallization techniques, by synthesis from optically activeprecursors, by chiral synthesis, by chromatographic separation using achiral stationary phase or by enzymatic resolution.

The compounds of present invention may also be present in differentsolid forms such as different crystalline forms or in the form of anamorphous solid. The present invention encompasses different crystallineforms as well as amorphous forms of the inventive compounds.

In addition, the compounds of the invention may exist as hydrates orsolvates, in which a certain stoichiometric amount of water or a solventis associated with the molecule in the crystalline form. The hydratesand solvates of the compounds of formula (I) are also the subject of theinvention.

Salts

In addition to the neutral compounds of formula (I), salt forms of thecompounds are also active against endoparasites. The term “veterinarilyacceptable salt” is used throughout the specification to describe anysalts of the compounds that are acceptable for administration forveterinary applications, and which provides the active compound uponadministration.

In cases where compounds are sufficiently basic or acidic to form stablenon-toxic acid or base salts, the compounds may be in the form of aveterinarily or agriculturally acceptable salt. Veterinarily acceptablesalts include those derived from veterinarily or agriculturallyacceptable inorganic or organic bases and acids. Suitable salts includethose comprising alkali metals such as lithium, sodium or potassium,alkaline earth metals such as calcium, magnesium and barium. Saltscomprising transition metals including, but not limited to, manganese,copper, zinc and iron are also suitable. In addition, salts comprisingammonium cations (NH₄ ⁺) as well as substituted ammonium cations, inwhich one or more of the hydrogen atoms are replaced by alkyl or arylgroups are encompassed by the invention.

Salts derived from inorganic acids including, but not limited to,hydrohalide acids (HCl, HBr, HF, HI), sulfuric acid, nitric acid,phosphoric acid, and the like are particularly suitable. Suitableinorganic salts also include, but not limited to, bicarbonate, andcarbonate salts. In some embodiments, examples of veterinarily andagriculturally acceptable salts are organic acid addition salts formedwith organic acids including, but not limited to, maleate, dimaleate,fumarate, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, andα-glycerophosphate. Of course, other acceptable organic acids may beused.

Alkali metal (for example, sodium, potassium or lithium) or alkalineearth metal (for example calcium) salts of the compounds can also bemade by reacting a sufficiently acidic residue on the compounds with ahydroxide of the alkali metal or alkaline earth metal.

Veterinarily acceptable salts may be obtained using standard procedureswell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitably acid functional group presentin the compound, or by reacting a suitable acid with a suitably basicfunctional group on the compound of the invention.

Processes for the Preparation of Compounds of Formula (I):

The compounds of formula (I) may be prepared by processes adapted fromthose described in U.S. Pat. Nos. 5,514,773; 5,747,448; 5,874,530;5,856,436; 6,033,879; 5,763,221; 6,329,338, 5,116,815; 6,468,966;6,369,028; 5,777,075; and 5,646,244, all which are hereby incorporatedby reference in their entirety. It will be appreciated by skilledpersons in the art that preparation of the compounds of the inventionhaving one or more inverted stereochemical centers compared with thenatural product PF1022A are made with the general process described inScheme 1 below except using intermediates having a stereochemicalconfiguration which results in compound having an invertedstereochemical configuration at the desired location in the moleculecompared. In addition, various synthetic methods for cyclicdepsipeptides have been reported in the chemical literature (seeLuttenberg et al., Tetrahedron 68 (2012), 2068-2073; Byung H. Lee,Tetrahedron Letters, 1997, 38 (5), 757-760; Scherkenbeck et al., Eur. J.Org. Chem., 2012, 1546-1553; Biosci. Biotech. Biochem., 1994, 58(6),1193-1194; and Scherkenbeck et al., Tetrahedron, 1995, 51(31),8459-8470) It will be understood by those skilled in the art thatcertain functional groups in the compounds and intermediates may beunprotected or protected by suitable protecting groups, as taught byGreene and Wuts, Protective Groups in Organic Synthesis, John Wiley andSons, Inc., 4^(th) edition 2006. Further, it will be apparent to thoseskilled in the art that the compounds and intermediates may be isolatedby standard aqueous work-up conditions and optionally purified. Forexample, the compounds or intermediates may be purified bychromatographic methods or crystallized to yield the desired product insuitable purity.

In one embodiment, the compounds of formula (I) where R¹, R², R³, R⁴,Cy¹ and Cy² are as defined above and R′, R″, R″′ and R″″ are methyl areprepared according to the general process described in Scheme 1 below.Modification of the stereochemical configuration of any of the carbonatoms bearing —CH₂Cy¹, —CH₂Cy², and/or the carbon atoms bearing R¹, R²,R³ and R⁴ provide the compounds of the invention.

P₁ and P₂ are amine and carboxylic acid protecting groups, respectively,commonly used in the art (see, for example, Greene and Wuts, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, Inc., 4th edition2006) and R¹, R², R³, R⁴, Cy¹ and Cy² are as defined above.

Furthermore, the coupling of amines with carboxylic acids to form amidesis well known in the art and standard reagents may be used in thecoupling of a fragment with an unprotected amine with a second fragmenthaving a free carboxylic acid group (see for example, Peptide Synthesisby Miklos Bodanszky and Miguel Ondetti, Interscience Publishers, 1966;Amino Acid and Peptide Synthesis, 2^(nd) Ed. By John Jones, OxfordUniversity Press, 2002). The compounds may be prepared by solution phasesynthesis or using solid-phase synthesis with polymeric supports. Forexample, the formation of amide bonds may be mediated by activatingreagents such as carbodiimide reagents (e.g. dicyclohexyldiimide,diisopropyldiimide and(N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide.HCl) in combination withadditives such as N-hydroxybenzotriazole (HOBt) and the like. Inaddition, the formation of amide bonds in the synthesis may beaccomplished by using phosphonium reagents such as BOP(Benzotriazol-1-yloxy-tris (dimethylamino)-phosphoniumhexafluorophosphate), PyBOP(Benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate),PyBrOP (Bromo-tripyrrolidino-phosphonium hexa-fluorophosphate) and thelike. Other useful reagents for forming the amide bonds of the compoundsof the invention are the so called aminium/uronium-imonium reagents suchas TBTU/HBTU (2-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetrafluoroborate/hexafluorophosphate), HATU(2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate) and the like. These reagents and the methodsemploying these reagents for the preparation of amide bonds are wellknown in the art.

Veterinary Compositions:

The compounds of formula (I) and compositions comprising the compoundsare useful for the prevention and treatment of parasiticinfestations/infections in animals. The compositions of the inventioncomprise an effective amount of at least one cyclic depsipeptidecompound of formula (I), or a veterinarily acceptable salt thereof, incombination with a veterinarily acceptable carrier or diluent andoptionally other non-active excipients. The compositions may be in avariety of solid and liquid forms which are suitable for various formsof application or administration to an animal. For example, theveterinary compositions comprising the inventive compounds may be informulations suitable for oral administration, injectableadministration, including subcutaneous and parenteral administration,and topical administration (e.g. spot-on or pour-on), dermal orsubdermal administration. The formulations are intended to beadministered to an animal including, but not limited to, mammals, birdsand fish. Examples of mammals include but are not limited to humans,cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, catsand other livestock or domestic mammals. Examples of birds includeturkeys, chickens, ostriches and other livestock or domestic birds. Theuse of the compounds of formula (I) to protect companion animals such asdogs and cats from endoparasites is particularly useful.

As discussed above, the compositions of the invention may be in a formsuitable for oral use (see, e.g., U.S. Pat. No. 4,564,631, which ishereby incorporated by reference in its entirety), dietary supplements,troches, lozenges, chewables, tablets, hard or soft capsules, bolus,emulsions, aqueous or oily suspensions, aqueous or oily solutions, oraldrench formulations, dispersible powders or granules, premixes, syrupsor elixirs, enteric formulations or pastes. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more sweetening agents, bittering agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (all incorporated herein by reference in theirentirety) to form osmotic therapeutic tablets for controlled release.

Oral formulations include hard gelatin capsules, wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin. Capsules may also be softgelatin capsules, wherein the active ingredient is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

In one embodiment, the compounds of formula (I) may be administered inchewable tablet compositions or soft chewable compositions such as thosedescribed in US 2013/0203692 A1, US 2010/0087492, US 2006/0222684, US2004/0151759, U.S. Pat. No. 7,955,632, all incorporated herein byreference. The veterinary compositions may be in the form of a softchewable formulation (“soft chew”) which is palatable and acceptable tothe animal. In addition to the active ingredient(s), the soft chews ofthe invention may include one or more of the following components: asolvent or mixture of solvents, one or more fillers, one or morebinders, one or more surfactants, one or more humectants, one or morelubricants, one or more disintegrants, one or more colorants, one ormore antimicrobial agents, one or more antioxidants, one or more pHmodifiers and one or more flavoring agents.

Solvents that may be used in the compositions of the invention include,but are not limited to, various grades of liquid polyethylene glycol(PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylenecarbonate; propylene glycol; triglycerides including, but not limited tocaprylic/capric triglyceride, caprylic/capric/linoleic triglyceride(e.g. MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride,propylene glycol dicaprylate/dicaprate, and the like; water, sorbitolsolution, glycerol caprylate/caprate and polyglycolized glycerides(GELUCIRE®), or a combination thereof.

Various fillers known in the art may be used in the soft chewablecompositions of the invention. Fillers include, but are not limited to,corn starch, pre-gelatinized corn starch, soy protein fines, corn cob,and corn gluten meal, and the like. In some embodiments, a combinationof two or more fillers may be used in the compositions.

Binders that may be used in the compositions of the invention include,but are not limited to, polyvinylpyrrolidone (e.g. Povidone),cross-linked polyvinylpyrrolidone (Crospovidone), polyethylene glycolsof various grades including PEG 3350, PEG 4000, PEG 6000, PEG 8000 andeven PEG 20,000, and the like; co-polymers of vinylpyrrolidone and vinylacetate (e.g. Copovidone) such as the product sold by BASF by thetradename Kollidon® VA 64 and the like; starch such as potato starch,tapioca starch or corn starch; molasses, corn syrup, honey, maple syrupand sugars of various types; or a combination of two or more binders.

Humectants that may be used in the compositions include, but are notlimited to, glycerol (also referred to herein as glycerin), propyleneglycol, cetyl alcohol and glycerol monostearate, and the like.Polyethylene glycols of various grades may also be used as humectants.

Surfactants may be present in the composition to improve theirsolubility and absorption after ingestion. Surfactants are typicallypresent in a concentration of about 1 to 10% (w/w), more typically about1 to about 5% (w/w). Examples of surfactants that may be used in thecompositions include, but are not limited to, glyceryl monooleate,polyoxyethylene sorbitan fatty acid esters, sorbitan esters includingsorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbatesincluding polysorbate 20 and polysorbate 80, d-α-tocopheryl polyethyleneglycol 1000 succinate (TPGS), sodium lauryl sulfate, co-polymers ofethylene oxide and propylene oxide (e.g. poloxamers such as LUTROL® F87and the like), polyethylene glycol castor oil derivatives includingpolyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castoroil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride estersincluding glycerol caprylate/caprate (CAPMUL® MCM), polyglycolizedglycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate, and the like.

The inventive formulations may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the formulation art. Antioxidants may be added to thecompositions of the invention to inhibit degradation of the activeagents. Suitable antioxidants include, but are not limited to, alphatocopherol, ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid,sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like.

The compositions of the invention may also include one or morelubricants and/or processing aids. In some cases, thelubricant/processing aid may also behave as a solvent, and accordingly,there some of the components of the inventive compositions may have dualfunctions. Lubricants/processing aids include, but are not limited topolyethylene glycols of various molecular weight ranges including PEG3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenatedvegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil.

Many flavoring agents may be used in the compositions of the inventionto improve the palatability of the oral veterinary formulations.Preferred flavoring agents are those that are not derived from animalsources. In various embodiments, flavoring components derived fromfruit, meat (including, but not limited to pork, beef, chicken, fish,poultry, and the like), vegetable, cheese, bacon, cheese-bacon and/orartificial flavorings may be used. A flavoring component is typicallychosen based upon consideration related to the organism that will beingesting the soft chew. For example, a horse may prefer an appleflavoring component, while a dog may prefer a meat flavoring component.Although flavoring components derived from non-animal sources arepreferred, in some embodiments, natural flavors containing beef or liverextracts, etc., may be used such as braised beef flavor artificialpowdered beef flavor, roast beef flavor and corned beef flavor amongothers.

In another embodiment of the invention, the active composition may beadministered via a drench, and may be administered either topically ororally. Drench formulations are those in which the liquid-containingcompositions of the invention are administered to the mouth or throat ofthe animal, or poured onto the skin or coat of the animal.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents include naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment, the composition of the invention may be in the formof a microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a cosurfactant. They aretranslucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets maybe less than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm may be composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase may be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase may be comprised oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasemay represent a % v/v range of about 2 to about 15%; about 7 to about10%; and about 8 to about 9% v/v of the microemulsion.

The aqueous phase may include, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment, the glycol may be propylene glycol,diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether ormixtures thereof. Generally, the aqueous phase will represent aproportion from about 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion may include diethylene glycolmonoethyl ether, dipropyelene glycol monomethyl ether, polyglycolyzedC₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to thesesurfactants, the cosurfactants may include short-chain alcohols, such asethanol and propanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and cosurfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofcosurfactant, there will be from about 25 to about 75% v/v of surfactantand from about 10 to about 55% v/v of cosurfactant in the microemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents include naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water may provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition may be in pasteform. Examples of embodiments in a paste form include, but are notlimited to, those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to thecompounds of the invention, the paste may further contain fumed silica;a viscosity modifier; a carrier; optionally, an absorbent; andoptionally, a colorant, stabilizer, surfactant, or preservative.

In one embodiment of the formulation, the formulation may be a pastecontaining the compounds of the invention, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which istriacetin, a monoglyceride, a diglyceride, or a triglyceride.

The paste may also include a viscosity modifier. Suitable viscositymodifiers include, but are not limited to, polyethylene glycols (PEG)including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600;monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),or poloxamers (e.g., Pluronic L 81); an absorbent such as magnesiumcarbonate, calcium carbonate, starch, and cellulose and its derivatives;and a colorant including, but not limited to, titanium dioxide ironoxide, or FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol, glycerol formal or polyethylene glycolsmay also be used. Preservatives, such as phenol or benzyl alcohol, maybe used.

In addition, sterile, fixed oils may be conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations may include, by way ofnon-limiting example, emulsions, creams, ointments, gels, pastes,powders, shampoos, pour-on formulations, ready-to-use formulations,spot-on solutions and suspensions, dips and sprays. Topical applicationof an inventive compound or of a composition including at least oneinventive compound among active agent(s) therein, in the form of aspot-on, spray-on or pour-on composition, may allow for the inventivecomposition to be absorbed through the skin to achieve systemic levels,distributed through the sebaceous glands or on the surface of the skinachieving levels throughout the coat. When the compound is distributedthrough the sebaceous glands, they may act as a reservoir, whereby theremay be a long-lasting effect (up to several months) effect. Spot-onformulations are typically applied in a localized region which refers toan area other than the entire animal. In one embodiment, the locationmay be between the shoulders. In another embodiment it may be a stripe,e.g. a stripe from head to tail of the animal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710, alsoincorporated herein by reference. Pour-on formulations may beadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g. an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include, but are notlimited to, acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, ethyl alcohol, butyl diglycol, dimethylacetamide,dimethylformamide, dimethyl sulfoxide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycolmonoethyl ether, ethylene glycol, triacetin, C₁-C₁₀ esters of carboxylicacids such as butyl or octyl acetate, and diethyl phthalate, or amixture of at least two of these solvents.

The solvent will be used in proportion with the concentration of theactive agent compound and its solubility in this solvent. It will besought to have the lowest possible volume. The vehicle makes up thedifference to 100%.

A vehicle or diluent for the formulations may include dimethyl sulfoxide(DMSO), glycol derivatives such as, for example, propylene glycol,glycol ethers, polyethylene glycols or glycerol. As vehicle or diluent,mention may also be made of plant oils such as, but not limited tosoybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil,grape seed oil, sunflower oil, etc.; mineral oils such as, but notlimited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclichydrocarbons or alternatively, for example, medium-chain (such as C₈ toC₁₂) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent may be added. In one embodiment, the emollientand/or spreading and/or film-forming agent may be:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,

(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetylsulphate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g. those derived from coconutoil),

(c) cationic surfactants include water-soluble quaternary ammonium saltsof formula N⁺R′R″R″′R″″, Y″ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y is an anion of a strong acidsuch as the halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,

(d) amine salts of formula N⁺HR′R″R″′ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,

(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or

(g) a mixture of at least two of these agents.

In one embodiment of the amount of emollient, the emollient used may bein a proportion of from about 0.1 to 50% or 0.25 to 5%, by volume. Inanother embodiment, the emollient used may be in a proportion of fromabout 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%,or about 5% to about 20% by volume.

In another embodiment of the invention, the composition may be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the compounds of theinvention, the ready-to-use solution may contain a crystallizationinhibitor and an organic solvent or a mixture of organic solvents. Insome embodiments, water may be included with the organic solvent.

In various embodiments of the invention, the compositions may include acrystallization inhibitor in an amount of about 1 to about 50% (w/v) orabout 5 to about 40% (w/v) based on the total weight of the formulation.In other embodiments, the amount of crystallization inhibitor in theinventive formulations may be about 1% to about 30%, about 5% to about20%, about 1% to about 15%, or about 1% to about 10% (w/w). The type ofcrystallization inhibitor used in the inventive formulations is notlimited as long as it functions to inhibit crystallization of the activeor inactive agents from the formulation. For example, in certainembodiments of the invention, a solvent or co-solvent of the formulationmay also function as a crystallization inhibitor if it sufficientlyinhibits the formation of crystals from forming over time when theformulation is administered.

Crystallization inhibitors which are useful for the invention include,but are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, mannitol, glycerol, sorbitol or polyoxyethylenatedesters of sorbitan; lecithin or sodium carboxymethylcellulose; oracrylic derivatives, such as acrylates or methacrylates or polymers orcopolymers thereof, polyethyleneglycols (PEG) or polymers containingpolyethyleneglycols, such as glycofurol and the like, and others;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulphates, which include but are notlimited to sodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R″′R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;

(d) amine salts of formula N⁺HR′R″R″′, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;

(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;

(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine;

(g) a mixture of at least two of the compounds listed in (a)-(f) above;or

(h) an organic solvent or mixture of solvents which inhibit theformation of crystals or amorphous solid after the formulation isadministered.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In some embodiments, the organic solvent(s) may have a dielectricconstant of between about 10 and about 35 or between about 20 and about30. In other embodiments, the organic solvent may have a dielectricconstant of between about 10 and about 40 or between about 20 and about30. The content of this organic solvent or mixture of solvents in theoverall composition is not limited and will be present in an amountsufficient to dissolve the desired components to a desiredconcentration. As discussed above, the organic solvent may also functionas a crystallization inhibitor in the formulation.

In some embodiments, one or more of the organic solvent(s) may have aboiling point of below about 100° C., or below about 80° C. In otherembodiments, the organic solvent(s) may have a boiling point of belowabout 300° C., below about 250° C., below about 230° C., below about210° C. or below about 200° C.

In some embodiments where there is a mixture of solvents, i.e. a solventand a co-solvent, the solvents may be present in the composition in aweight/weight (W/W) ratio of about 1/50 to about 1/1. Typically thesolvents will be in a ratio of about 1/30 to about 1/1, about 1/20 toabout 1/1, or about 1/15 to about 1/1 by weight. Preferably, the twosolvents will be present in a weight/weight ratio of about 1/15 to about1/2. In some embodiments, at least one of the solvents present may actas to improve solubility of the active agent or as a drying promoter. Inparticular embodiments, at least one of the solvents will be misciblewith water.

The formulation may also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent may be present in a proportion ofabout 0.005 to about 1% (w/v), about 0.01 to about 0.1%, or about 0.01to about 0.05%.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent may be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The crystallization inhibitor inhibits the formation of crystals on thecoat, and improves the maintenance of the cosmetic appearance of theskin or fur; that is to say without a tendency towards sticking ortowards a sticky appearance, despite the high concentration of activematerial. Substances other than those mentioned herein may be used ascrystallization inhibitors in the present invention. In one embodiment,the effectiveness of the crystallization inhibitor may be demonstratedby a test according to which 0.3 mL of a solution comprising 10% (w/v)of the active agent in an appropriate solvent as defined above, and 10%(w/v) of the compound acting as a crystallization inhibitor are placedon a glass slide at 20° C. for 24 hours, after which fewer than 10crystals, preferably 0 crystals, are seen with the naked eye on theglass slide.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but are not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of atleast two compounds with antioxidant properties.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume of the formulation applied will depend on the type of animaland the size of the animal as well as the strength of the formulationand the potency of the active agents. In one embodiment, an amount ofabout 0.1 to about 20 ml of the formulation may be applied to theanimal. In other embodiment for the volume, the volume may be about 0.1to about 10 ml, about 0.1 to about 5 ml, about 0.5 ml to about 10 ml, orabout 0.3 to about 3 ml.

In another embodiment of the invention, application of a spot-onformulation according to the present invention may also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier may be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation may comprise asolvent or mixture of solvents including, but not limited to, acetone,an aliphatic alcohol such as methanol, ethanol, propanol, butanol,isopropanol, pentanol, hexanol, heptanol, octanol, nonanol,cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol and thelike; an aromatic alcohol such as phenol, cresol, naphthol, benzylalcohol and the like; acetonitrile, butyl diglycol, an organic amidesuch as dimethylacetamide, dimethylformamide, monomethylacetamide,2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone and the like;propylene or ethylene carbonate, dimethylsulfoxide (DMSO), a glycolpolymer or an ether thereof, such as polyethylene glycol (PEG) ofvarious grades, polypropylene glycols of various grades, dipropyleneglycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycolmonomethyl ether, dipropylene glycol monomethyl ether, diethylene glycolmonoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters,such as the diethyl ester or diisobutyl adipate, or a mixture of atleast two of these solvents.

The liquid carrier vehicle may optionally contain a crystallizationinhibitor including, but not limited to, those described in (a) to (h)above, or a compound that may act both as a solvent and acrystallization inhibitor (as defined above), or a mixture of thesecrystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation may be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may typically contain from about 0.1 mg to about 5 g. Inother embodiments, the dosage form may contain about 0.5 mg to about 5 gof an active agent. In one embodiment of the dosage form, the dosage maycontain from about 1 mg to about 500 mg of an active agent, typicallyabout 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000mg.

In one embodiment of the invention, the active agent may be present inthe formulation at a concentration of about 0.05 to about 10%weight/volume. In another embodiment of the invention, the active agentmay be present in the formulation as a concentration from about 0.1 toabout 2% weight/volume. In yet another embodiment of the invention, theactive agent may be present in the formulation as a concentration fromabout 0.25 to about 1.5% weight/volume. In still another embodiment ofthe invention, the active agent may be present in the formulation as aconcentration about 1% weight/volume.

II. Methods of Treatment:

As discussed above, the compounds of formula (I) are effective againstendoparasites and may be used to treat and prevent parasitic infectionsin or on animals. In one embodiment, the present invention provides amethod of treating or preventing an endoparasite infection in or on ananimal (e.g. a mammal or bird) comprising administering anendoparasiticidally effective amount of a compound of formula (I), orveterinarily acceptable salts thereof, or a composition of theinvention, to the animal.

In various embodiments of the invention, depsipeptide of formula (I) maybe included in the composition to deliver a dose of about 0.001 mg/kg toabout 50 mg/kg or about 0.5 mg/kg to about 50 mg/kg of body weight ofthe animal. In other embodiments, the active agent will typically bepresent in an amount sufficient to deliver a dose of about 0.05 mg/kg toabout 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments,the active agent will be present in an amount sufficient to deliver adose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1mg/kg or about 0.5 mg/kg to about 50 mg/kg per body weight of theanimal.

In certain embodiments of the invention the depsipeptide compound offormula (I) will be present in a concentration to provide a dose ofabout 0.001 mg/kg to about 5 mg/kg, about 0.001 mg/kg to about 0.1 mg/kgor about 0.001 mg/kg to about 0.01 mg/kg. In still other embodiments,the compound of formula (I) will be present in an amount sufficient todeliver a dose of about 0.01 mg/kg to about 2 mg/kg or about 0.1 mg/kgto about 1 mg/kg per body weight of the animal. In still otherembodiments, the compound of formula (I) may be present in an amount todeliver a dose of about 1 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal.

The compounds of formula (I) may also effective against ectoparasitesand may be used to treat and prevent ectoparasitic infestations onanimals. In another embodiment, the present invention provides a methodof treating or preventing an ectoparasitic infestation on an animal(e.g. a mammal or bird) comprising administering an ectoparasiticidallyeffective amount of a compound of formula (I), or veterinarilyacceptable salts thereof, or a composition of the invention, to theanimal.

In another embodiment, the invention provides a method for treating orpreventing an endoparasitic infection and an ectoparasitic infestationin and on an animal, comprising administering a composition comprisingan effective amount of a compound of formula (I) in combination with aneffective amount of at least a second active agent, or veterinarilyacceptable salts thereof, to the animal.

In still another embodiment of the invention, a method is provided forthe treatment or prevention of a parasitic infestation at a locus, whichcomprises administering or applying a parasiticidally effective amountof a compound of formula (I), or veterinarily acceptable salts thereof,to the locus. With respect to animal health applications, “locus” isintended to mean a habitat, breeding ground, area, material orenvironment in which a parasite is growing or may grow, excluding in oron an animal.

In another embodiment, the invention provides methods and uses of thecompounds of formula (I) for controlling pests in plants and crops orfor protecting wood-containing structures.

Mammals which can be treated include but are not limited to humans,cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas,camels, pigs, sheep and yaks. In one embodiment of the invention, themammals treated are humans, cats or dogs.

In one embodiment of the invention, the compounds of formula (I) havebeen superior efficacy against endoparasites, and in particular againstendoparasites that are resistant to active agents of the macrocycliclactone class. In one embodiment, the compounds and compositions of theinvention are effective for controlling Haemonchus contortus, Ostertagiacircumcincta and Trichostrongylus colubriformis in mammals or birds.

In another embodiment, the invention provides a method for treating anparasitic infestation or infection in an animal, comprisingadministering an effective amount of an anthelmintic compound of theinvention in combination with an effective amount of activators ofinvertebrate GABA receptors including an avermectin or milbemycin to theanimal in need thereof. Avermectins that may be used in combination withthe compounds of the invention include, but are not limited toabamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin, and selamectin Milbemycins compounds that may beused in combination with the compounds of the invention include, but arenot limited to, milbemectin, milbemycin D, moxidectin and nemadectin.Also included are the 5-oxo and 5-oxime derivatives of said avermectinsand milbemycins.

In one embodiment, the compounds and compositions of the invention maybe used for treating or preventing an endoparasitic infection of thefollowing parasite: Anaplocephala (Anoplocephala), Ancylostoma, Necator,Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia,Cyathostomum, Cylicocyclus, Cylicodontophorus, Cylicostephanus,Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium, Dirofilaria,Dracunculus, Echinococcus, Enterobius, Fasciola, Filaroides, Habronema,Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus,Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris,Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides,Toxascaris, Trichinella, Trichuris, Trichostrongylus, Triodontophorus,Uncinaria, Wuchereria, and combinations thereof.

In a particularly preferred embodiment of the invention, the compoundsand compositions of the invention are used to treat or prevent aninfection by Dirofilaria immitis. The compounds of formula (I) have beenfound to be highly effective against D. immitis microfilaria and L4larvae. Thus, the compounds of formula (I) may be used to protectanimals from developing heartworm disease by killing the immature stagesof D. immitis before they can develop into adult worms. In oneembodiment, the compounds of formula (I) and compositions comprising thecompounds may be used to prevent the development of heartworm disease bykilling immature stages of D. immitis that are resistant to macrocycliclactones. In another embodiment the compounds and compositions of theinvention are used to treat or prevent an infection by Dirofilariarepens or Dirofilaria hongkongensis.

In another embodiment of the invention, the parasite is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battusand combinations thereof.

In another embodiment for treatment against both endoparasites andectoparasites when combined with ectoparasiticidal agents, theectoparasite is one or more insect or arachnid including those of thegenera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus,Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes,Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes,Trichodectes, and Felicola.

In another embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor, Ixodes and/or Boophilus. The ectoparasites treated includebut are not limited to fleas, ticks, mites, mosquitoes, flies, lice,blowfly and combinations thereof. Specific examples include but are notlimited to cat and dog fleas (Ctenocephalides felis, Ctenocephalidesspp. and the like), ticks (Rhipicephalus spp., Ixodes spp., Dermacentorspp., Amblyomma spp. and the like), and mites (Demodex spp., Sarcoptesspp., Otodectes spp. and the like), lice (Trichodectes spp.,Cheyletiella spp., Linognathus spp., and the like), mosquitoes (Aedesspp., Culex spp., Anopheles spp., and the like) and flies (Haematobiaspp., Musca spp., Stomoxys spp., Dermatobia spp., Cochliomyia spp., andthe like). In yet another embodiment for the treatment againstectoparasites, the ectoparasite is a flea and/or tick.

Additional examples of ectoparasites include but are not limited to thetick genus Boophilus, especially those of the species microplus (cattletick), decoloratus and annulatus; myiasis such as Dermatobia hominis(known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle);sheep myiasis such as Lucilia sericata, Lucilia cuprina (known asblowfly strike in Australia, New Zealand and South Africa). Fliesproper, namely those whose adult constitutes the parasite, such asHaematobia irritans (horn fly); lice such as Linognathus vitulorum,etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis. The abovelist is not exhaustive and other ectoparasites are well known in the artto be harmful to animals and humans. These include, for examplemigrating dipterous larvae.

In another embodiment of the invention, the compounds and compositionsof the invention are suitable for controlling pests such as insectsselected from the group consisting of Blatella germanica, Heliothisvirescens, Leptinotarsa decemlineata, Tetramorium caespitum andcombinations thereof.

The phytoparasitic nematodes include, for example, Anguina spp.,Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchusdipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp.,Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholussimilis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp.,Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.

In addition, with or without the other pesticidal agents added to thecomposition, the invention can also be used to treat other pests whichinclude but are not limited to pests:

(1) from the order of Isopoda, for example Oniscus asellus,Armadillidium vulgare and Porcellio scaber;

(2) from the order of Diplopoda, for example Blaniulus guttulatus;

(3) from the order of Chilopoda, for example Geophilus carpophagus andScutigera spp.;

(4) from the order of Symphyla, for example Scutigerella immaculata;

(5) from the order of Thysanura, for example Lepisma saccharina;

(6) from the order of Collembola, for example Onychiurus armatus;

(7) from the order of Blattaria, for example Blatta orientalis,Periplaneta americana, Leucophaea maderae and Blattella germanica;

(8) from the order of Hymenoptera, for example Diprion spp., Hoplocampaspp., Lasius spp., Monomorium pharaonis and Vespa spp.;

(9) from the order of Siphonaptera, for example Xenopsylla cheopis andCeratophyllus spp.;

(10) from the order of Anoplura (Phthiraptera), for example, Damaliniaspp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectesspp.;

(11) from the class of Arachnida, for example, Acarus siro, Aceriasheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp.,Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp.,Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri,Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp.,Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychusspp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora,Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp.,Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp.,Tarsonemus spp., Tetranychus spp., Vasates lycopersici.;

(12) from the class of Bivalva, for example, Dreissena spp.;

(13) from the order of Coleoptera, for example, Acanthoscelidesobtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallonsolstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp.,Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidiusobtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderusspp., Cosmopolites spp., Costelytra zealandica, Curculio spp.,Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp.,Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorphaelegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp.,Lachnosterna consanguinea, Leptinotarsa decemlineata, Lissorhoptrusoryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolonthamelolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus,Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis,Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae,Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodeschrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica,Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp.,Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp.,Xylotrechus spp., Zabrus spp.;

(14) from the order of Diptera, for example, Aedes spp., Anopheles spp.,Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata,Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp.,Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fanniaspp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp.,Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp.,Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanusspp., Tannia spp., Tipulapaludosa, Wohlfahrtia spp.;

(15) from the class of Gastropoda, for example, Arion spp., Biomphalariaspp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp.,Oncomelania spp., Succinea spp.;

(16) from the class of helminths, for example, Ancylostoma duodenale,Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma spp.,Ascaris lumbricoides, Ascaris spp., Brugia malayi, Brugia timori,Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp.,Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum,Dracunculus medinensis, Echinococcus granulosus, Echinococcusmultilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp.,Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa,Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocercavolvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp.,Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloidesspp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinellanativa, Trichinella britovi, Trichinella nelsoni, Trichinellapseudopsiralis, Trichostrongulus spp., Trichuris trichiura, Wuchereriabancrofti.;

(17) from the order of Heteroptera, for example, Anasa tristis,Antestiopsis spp., Blissus spp., Calocoris spp., Camnpylomma livida,Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis,Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistusspp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisaspp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae,Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp.,Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergellasingularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatomaspp.;

(18) from the order of Homoptera, for example, Acyrthosipon spp.,Aeneolanmia spp., Agonoscena spp., Aleurodes spp., Aleurolobusbarodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui,Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis,Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani,Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicorynebrassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacunalanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii,Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola,Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp.,Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp.,Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccusspp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelisbilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterusarundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphaxstriatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi,Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari,Metcalfiella spp., Metopolophium dirhodum, Monellia costalis,Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettixspp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga,Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp.,Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodonhumuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp.,Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcusspp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp.,Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp.,Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus,Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina,Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp.,Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp.,Unaspis spp., Viteus vitifolii.;

(19) from the order of Isoptera, for example, Reticulitermes spp.,Odontotermes spp.;

(20) from the order of Lepidoptera, for example, Acronicta major, Aedialeucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathrabrassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana,Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp.,Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Eariasinsulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp.,Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp.,Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella,Laphygma spp., Lithocolletis blancardella, Lithophane antennata,Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestrabrassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae,Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella,Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp.,Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesiagemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana,Trichoplusia spp.;

(21) from the order of Orthoptera, for example, Acheta domesticus,Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaeamaderae, Locusta spp., Melanoplus spp., Periplaneta americana,Schistocerca gregaria.;

(22) from the order of Thysanoptera, for example, Baliothrips biformis,Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothripsfemoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothripsspp., Taeniothrips cardamoni, Thrips spp.;

(23) from the class of Protozoa, for example, Eimeria spp.

In each aspect of the invention, the compounds and compositions of theinvention can be applied against a single pest or combinations thereof.

III. Mixtures with Other Active Agents

In another embodiment, the compositions comprising the cyclicdepsipeptides of formula (I) may also include other veterinarytherapeutic agents. Veterinary pharmaceutical agents that may beincluded in the compositions of the invention are well-known in the art(see e.g. Plumb' Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C.Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual,9^(th) Edition, (January 2005)) and include but are not limited toacarbose, acepromazine maleate, acetaminophen, acetazolamide,acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine,acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil,allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate,aminocaproic acid, aminopentamide hydrogen sulfate,aminophylline/theophylline, amiodarone, amitriptyline, amlodipinebesylate, ammonium chloride, ammonium molybdenate, amoxicillin,clavulanate potassium, amphotericin B desoxycholate, amphotericin Blipid-based, ampicillin, amprolium, antacids (oral), antivenin,apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspiring,atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin,aurothioglucose, azaperone, azathioprine, azithromycin, baclofen,barbituates, benazepril, betamethasone, bethanechol chloride, bisacodyl,bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate,bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone,busulfan, butorphanol tartrate, cabergoline, calcitonin salmon,calcitrol, calcium salts, captopril, carbenicillin indanyl sodium,carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil,cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaximesodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil,ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin,cephalosporins, cephapirin, charcoal (activated), chlorambucil,chloramphenicol, chlordiazepoxide, chlordiazepoxide+/−clidinium bromide,chlorothiazide, chlorpheniramine maleate, chlorpromazine,chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG),chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citratesalts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin,clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium,clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate,colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide,cyclosporine, cyproheptadine, cytarabine, dacarbazine,dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolenesodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib,deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate,detomidine, dexamethasone, dexpanthenol, dexraazoxane, dextran,diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium,dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES),difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem,dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprosttromethamine, diphenylhydramine, disopyramide phosphate, dobutamine,docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin,doxapram, doxepin, doxorubicin, doxycycline, edetate calciumdisodium.calcium EDTA, edrophonium chloride, enalapril/enalaprilat,enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine,epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin,esmolol, estradiol cypionate, ethacrynic acid/ethacrynate sodium,ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasiaagents w/pentobarbital, famotidine, fatty acids (essential/omega),felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil,florfenicol, fluconazole, flucytosine, fludrocortisone acetate,flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU),fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole(4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicinsulfate, glimepiride, glipizide, glucagon, glucocorticoid agents,glucosamine/chondroitin sulfate, glutamine, glyburide, glycerine (oral),glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane,hemoglobin glutamer-200 (OXYGLOBIN®®), heparin, hetastarch, hyaluronatesodium, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate,hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide,imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium,imipramine, inamrinone lactate, insulin, interferon alfa-2a (humanrecombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium,iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine,itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole,ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole,levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyroninesodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium,mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid,medetomidine, medium chain triglycerides, medroxyprogesterone acetate,megestrol acetate, melarsomine, melatonin, meloxican, melphalan,meperidine, mercaptopurine, meropenem, metformin, methadone,methazolamide, methenamine mandelate/hippurate, methimazole, methionine,methocarbamol, methohexital sodium, methotrexate, methoxyflurane,methylene blue, methylphenidate, methylprednisolone, metoclopramide,metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam milbemycinoxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone,morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen,narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine,niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin,nitroprusside sodium, nizatidine, novobiocin sodium, nystatin,octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiateantidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxibutyninchloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium,pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine,pencillamine, general information penicillins, penicillin G, penicillinV potassium, pentazocine, pentobarbital sodium, pentosan polysulfatesodium, pentoxifylline, pergolide mesylate, phenobarbital,phenoxybenzamine, pheylbutazone, phenylephrine, phenypropanolamine,phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitaminK-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfatedglycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride,prazosin, prednisolone/prednisone, primidone, procainamide,procarbazine, prochlorperazine, propantheline bromide, Propionibacteriumacnes injection, propofol, propranolol, protamine sulfate,pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide,pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine,rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative,selamectin, selegiline/1-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles may be included in the veterinary compositions of theinvention. Arylpyrazoles are known in the art and are suitable forcombination with the cyclic depsipeptides of formula (I) in thecompositions of the invention. Examples of such arylpyrazole compoundsinclude but are not limited to those described in U.S. Pat. Nos.6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954,6,998,131 and 7,759,381 (all of which are incorporated herein byreference). A particularly preferred arylpyrazole active agent isfipronil.

In another embodiment of the invention, one or more macrocycliclactones, which act as an acaricide, an anthelmintic agent and/or aninsecticide, can be included in the compositions of the invention incombination with the compounds of formula (I). For the avoidance ofdoubt, the term “macrocyclic lactone” as used herein includes bothnaturally occurring and synthetic or semi-synthetic avermectin andmilbemycin compounds.

The macrocyclic lactones that may be used in the compositions of theinvention include, but are not limited to, the naturally producedavermectins (e.g. including the components designated as A₁a, A₁b, A₂a,A₂b, B₁a, Bib, B₂a and B₂b) and milbemycin compounds, semisyntheticavermectins and milbemycins, avermectin monosaccharide compounds andavermectin aglycone compounds. Examples of macrocyclic lactone compoundsthat may be used in the compositions include, but are not limited to,abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin, selamectin, ML-1,694,554 and milbemycinsincluding, but not limited to, milbemectin, milbemycin D, milbemycin A₃,milbemycin A₄, milbemycin oxime, moxidectin and nemadectin. Alsoincluded are the 5-oxo and 5-oxime derivatives of said avermectins andmilbemycins.

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schonberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054, both incorporated herein by reference.

The structure of the avermectins and milbemycins are closely related,e.g., by sharing a complex 16-membered macrocyclic lactone ring. Thenatural product avermectins are disclosed in U.S. Pat. No. 4,310,519 andthe 22,23-dihydro avermectin compounds are disclosed in U.S. Pat. No.4,199,569. Mention is also made of U.S. Pat. Nos. 4,468,390, 5,824,653,EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP 0 002 916, andNew Zealand Patent No. 237 086, inter alia. Naturally occurringmilbemycins are described in U.S. Pat. No. 3,950,360 as well as in thevarious references cited in “The Merck Index” 12^(th) ed., S. Budavari,Ed., Merck & Co., Inc. Whitehouse Station, N.J. (1996). Latidectin isdescribed in the “International Nonproprietary Names for PharmaceuticalSubstances (INN)”, WHO Drug Information, vol. 17, no. 4, pp. 263-286,(2003). Semisynthetic derivatives of these classes of compounds are wellknown in the art and are described, for example, in U.S. Pat. Nos.5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749,4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677,4,920,148 and EP 0 667 054, all incorporated herein by reference.

In one embodiment, the veterinary compositions of the invention comprisean effective amount of at least one of abamectin, dimadectin,doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin,selamectin, milbemectin, milbemycin D, milbemycin A₃, milbemycin A₄,milbemycin oxime, moxidectin or nemadectin, or a combination thereof. Inanother embodiment, the invention provides a veterinary compositioncomprising an effective amount of at least one of abamectin, emamectin,eprinomectin, ivermectin, doramectin or selamectin, or a combinationthereof. In still another embodiment, the veterinary compositions of theinvention comprise an effective amount of at least one of ivermectin,milbemectin, milbemycin oxime or moxidectin, or a combination thereof.

In another embodiment of the invention, a composition comprising acompound of formula (I) in combination with a class of acaricide orinsecticides known as insect growth regulators (IGRs) are provided.Compounds belonging to this group are well known to the practitioner andrepresent a wide range of different chemical classes. These compoundsall act by interfering with the development or growth of the insectpests. Insect growth regulators are described, for example, in U.S. Pat.Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022or U.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (allincorporated herein by reference).

In one embodiment the compositions of the invention may include an IGRcompound that mimics juvenile hormone or that modulates levels ofjuvenile hormones in insects. Examples of juvenile hormone mimicsinclude azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen, tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.In another embodiment, the compositions of the invention comprise acompound of formula (I) in combination with methoprene or pyriproxyfenand a pharmaceutically acceptable carrier.

In another embodiment, the compositions of the invention include an IGRcompound that is a chitin synthesis inhibitor. Chitin synthesisinhibitors include chlorofluazuron, cyromazine, diflubenzuron,fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron,tebufenozide, teflubenzuron, triflumoron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In some embodiments, the compositions of the invention may include oneor more antinematodal agents including, but not limited to, activeagents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidinesand the organophosphate class of compounds. In some embodiments,benzimidazoles including, but not limited to, thiabendazole,cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole,fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel,thiophanate and its o,o-dimethyl analogue may be included in thecompositions.

In other embodiments, the compositions of the invention may include animidazothiazole compounds including, but not limited to, tetramisole,levamisole and butamisole.

In still other embodiments, the compositions of the invention mayinclude tetrahydropyrimidine active agents including, but not limitedto, pyrantel, oxantel, and morantel.

Suitable organophosphate active agents include, but are not limited to,coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos,mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the compositions may include the antinematodalcompounds phenothiazine, piperazine as the neutral compound and invarious salt forms, diethylcarbamazine, phenols such as disophenol,arsenicals such as arsenamide, ethanolamines such as bephenium, theniumclosylate, and methyridine; cyanine dyes including pyrvinium chloride,pyrvinium pamoate and dithiazanine iodide; isothiocyanates includingbitoscanate, suramin sodium, phthalofyne, and various natural productsincluding, but not limited to, hygromycin B, ca-santonin and kainicacid.

In other embodiments, the compositions of the invention may includeantitrematodal agents. Suitable antitrematodal agents include, but arenot limited to, the miracils such as miracil D and mirasan;praziquantel, clonazepam and its 3-methyl derivative, oltipraz,lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil,various bisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, nitroxynil, brotianide, bromoxanide andclosantel; triclabendazole, diamfenetide, clorsulon, hetolin andemetine.

Anticestodal compounds may also be advantageously used in thecompositions of the invention including, but not limited to, arecolinein various salt forms, bunamidine, niclosamide, nitroscanate,paromomycin, paromomycin II, praziquantel and epsiprantel.

In yet other embodiments, the compositions of the invention may includeother active agents that are effective against arthropod parasites.Suitable active agents include, but are not limited to, bromocyclen,chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos,bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos,crotoxyphos, cythioate, diazinon, dichlorenthion, diemthoate,dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate,iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos,ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin,fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins,resmethrin, benzyl benzoate, carbon disulfide, crotamiton,diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate,methoprene, monosulfiram, pirenonylbutoxide, rotenone, triphenyltinacetate, triphenyltin hydroxide, deet, dimethyl phthalate, and thecompounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde(MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

In another embodiment, an antiparasitic agent that can be included inthe veterinary composition containing a compound of formula (I) can be abiologically active peptide or protein including, but not limited to,depsipeptides other than the compounds of formula (I). These includePF1022A or analogs thereof and emodepside. These compounds act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside (see Wilson et al., Parasitology, January 2003, 126(Pt1):79-86).

In another embodiment, the compositions of the invention may comprise anactive agent from the neonicotinoid class of parasiticides. Theneonicotinoids bind and inhibit insect specific nicotinic acetylcholinereceptors. In one embodiment, the neonicotinoid insecticidal agent thatcan be combined with a compound of formula (I) in a composition of theinvention is imidacloprid. Agents of this class are described, forexample, in U.S. Pat. No. 4,742,060 or in EP 0 892 060 (bothincorporated herein by reference). In another embodiment, thecompositions of the invention may comprise nitenpyram, another activeagent of the neonicotinoid class of pesticides. The use of nitenpyramfor controlling fleas is described in U.S. Pat. No. 5,750,548, which isincorporated herein by reference in its entirety.

In certain other embodiments of the invention, the cyclic depsipeptidesof formula (I) can be combined with the compositions of the invention isa semicarbazone, such as metaflumizone.

In another embodiment, the compositions of the invention mayadvantageously include a one or more pesticidal isoxazoline compoundsknown in the art. Isoxazoline active agents are highly effective againsta variety of ectoparasites and combination of an isoxazoline activeagent with the cyclic depsipeptides of formula (I) would expand thescope of efficacy against these parasites. Particularly usefulisoxazoline active agents that can be combined with the compounds offormula (I) include afoxolaner (including substantially pure activeenantiomer), sarolaner, fluralaner (including substantially pure activeenantiomer) and lotilaner. These active agents are described in U.S.Pat. No. 7,964,204, US 2010/0254960 A1, US2011/0159107, US2012/0309620,US2012/0030841, US2010/0069247, WO 2007/125984, WO 2012/086462, U.S.Pat. Nos. 8,318,757, 8,466,115, 8,618,126, 8,822,466, 8,383,659,8,853,186, 9,221,835, US 2011/0144349, U.S. Pat. No. 8,053,452; US2010/0137612, U.S. Pat. No. 8,410,153, US 2011/152081, WO 2012/089623,WO 2012/089622, U.S. Pat. Nos. 8,119,671; 7,947,715; WO 2102/120135, WO2012/107533, WO 2011/157748, US 2011/0245274, US 2011/0245239, US2012/0232026, US 2012/0077765, US 2012/0035122, US 2011/0251247, WO2011/154433, WO 2011/154434, US 2012/0238517, US 2011/0166193, WO2011/104088, WO 2011/104087, WO 2011/104089, US 2012/015946, US2009/0143410, WO 2007/123855 A2, US 2011/0118212, U.S. Pat. No.7,951,828 & U.S. Pat. No. 7,662,972, US 2010/0137372 A1, US 2010/0179194A2, US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1, US2015/0126523, WO 2010/003923, WO 2010/003877, WO 2010/072602, WO2014/134236, U.S. Pat. Nos. 7,897,630, and 7,951,828, all of which areincorporated herein by reference in their entirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives may be added to the compositions of the invention. Thesecompounds are used to treat or prevent infections in humans and animalsand are described, for example, in U.S. Pat. Nos. 5,399,582, 5,962,499,6,221,894 and 6,399,786, all of which are hereby incorporated byreference in their entirety. The compositions may include one or more ofthe known nodulisporic acid derivatives in the art, including allstereoisomers, such as those described in the literature cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX) and the like may beadded to the compositions of the invention. These compounds aredescribed, for example, in U.S. Pat. No. 7,084,280 to Ducray et al.(incorporated herein by reference); Sager et al., VeterinaryParasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13Mar. 2008, 176-181.

The compositions of the invention may also include aryloazol-2-ylcyanoethylamino compounds such as those described in U.S. Pat. No.8,088,801 to Soll et al., which is incorporated herein by reference, andthioamide derivatives of these compounds, as described in U.S. Pat. No.7,964,621 to Le Hir de Fallois, which is also incorporated herein byreference.

Aryloazol-2-yl cyanoethylamino active agents, which aresystemically-acting against endoparasites, may be used in combinationwith the compounds of formula (I) in veterinary compositions of theinvention.

The compositions of the invention may also include paraherquamidecompounds and derivatives of these compounds, including derquantel (seeOstlind et al., Research in Veterinary Science, 1990, 48, 260-61; andOstlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408).The paraherquamide family of compounds is a known class of compoundsthat include a spirodioxepino indole core with activity against certainparasites (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380,and J. Antibiotics 1991, 44, 492). In addition, the structurally relatedmarcfortine family of compounds, such as marcfortines A-C, are alsoknown and may be combined with the formulations of the invention (see J.Chem. Soc.—Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Furtherreferences to the paraherquamide derivatives can be found, for example,in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432 andUS 2010/0197624, U.S. Pat. Nos. 5,703,078 and 5,750,695, all of whichare hereby incorporated by reference in their entirety.

In another embodiment of the invention, the compositions may include aspinosyn active agent produced by the soil actinomyceteSaccharopolyspora spinosa (see, for example Salgado V. L. and Sparks T.C., “The Spinosyns: Chemistry, Biochemistry, Mode of Action, andResistance,” in Comprehensive Molecular Insect Science, vol. 6, pp.137-173, 2005) or a semi-synthetic spinosoid active agent. The spinosynsare typically referred to as factors or components A, B, C, D, E, F, G,H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of thesecomponents, or a combination thereof, may be used in the compositions ofthe invention. The spinosyn compound may be a 5,6,5-tricylic ringsystem, fused to a 12-membered macro cyclic lactone, a neutral sugar(rhamnose), and an amino sugar (forosamine). These and other naturalspinosyn compounds, including 21-butenyl spinosyn produced bySaccharopolyspora pagona, which may be used in the compositions of theinvention, may be produced via fermentation by conventional techniquesknown in the art. Other spinosyn compounds that may be used in thecompositions of the invention are disclosed in U.S. Pat. Nos. 5,496,931;5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861;5,670,486; 5,631,155 and 6,001,981, all incorporated by reference hereinin their entirety. The spinosyn compounds may include, but are notlimited to, spinosyn A, spinosyn D, spinosad, spinetoram, orcombinations thereof. Spinosad is a combination of spinosyn A andspinosyn D, and spinetoram is a combination of 3′-ethoxy-5,6-dihydrospinosyn J and 3′-ethoxy spinosyn L.

In general, additional active agents (other than the compound of formula(I) described above) is included in the dosage units of the invention inan amount of between about 0.1 μg and about 1000 mg. Typically, theactive agent may be included in an amount of about 10 μg to about 500mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mgto about 200 mg or about 10 mg to about 100 mg. More typically theadditional active agent will be present in an amount of about 5 mg toabout 50 mg in the compositions of the invention.

The concentration of the additional active agent in the compositions ofthe invention will typically be from about 0.01% to about 30% (w/w)depending on the potency of the active agent. In certain embodiments forvery potent active agents including, but not limited to a macrocycliclactone active agent, the concentration of the active agent willtypically be from about 0.01% to about 10% (w/w), from about 0.01 toabout 1% (w/w), from about 0.01% to about 0.5% (w/w), from about 0.1% toabout 0.5% (w/w) or from about 0.01% to about 0.1% (w/w). In otherembodiments, the concentration of the active agent will typically befrom about 0.1% to about 2% (w/w) or about 0.1% to about 1% (w/w).

In other embodiments, the additional active agent will typically bepresent at higher concentrations to achieve the desired efficacy. Insome embodiments, the active agent will be present in a concentration ofabout 1% to about 30% (w/w), about 1% to about 20% (w/w) or about 1% toabout 15% (w/w). In still other embodiments, the active agent will bepresent in a concentration of about 5% to about 20% (w/w) or about 5% toabout 15% (w/w) in the composition.

In various embodiments of the invention, an additional active agent maybe included in the composition to deliver a dose of about 0.001 mg/kg toabout 50 mg/kg or about 0.5 mg/kg to about 50 mg/kg of body weight ofthe animal. In other embodiments, the active agent will typically bepresent in an amount sufficient to deliver a dose of about 0.05 mg/kg toabout 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments,the active agent will be present in an amount sufficient to deliver adose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1mg/kg or about 0.5 mg/kg to about 50 mg/kg per body weight of theanimal. In certain embodiments of the invention where the additionalactive agent is a very potent compound such as a macrocyclic lactone orother potent compounds, the active agent will be present in aconcentration to provide a dose of about 0.001 mg/kg to about 5 mg/kg,about 0.001 mg/kg to about 0.1 mg/kg or about 0.001 mg/kg to about 0.01mg/kg. In still other embodiments, the active agent is present in anamount sufficient to deliver a dose of about 0.01 mg/kg to about 2 mg/kgor about 0.1 mg/kg to about 1 mg/kg per body weight of the animal. Instill other embodiments, the additional active agent may be present inan amount to deliver a dose of about 1 μg/kg to about 200 μg/kg or about0.1 mg/kg to about 1 mg/kg of weight of animal.

In addition to the other active agents mentioned above, combinations oftwo or more active agents may be used with the compounds of theinvention in a composition to treat a desired spectrum of pests andparasites. It would be well within the skill level of the practitionerto decide which individual compound can be used in the inventiveformulation to treat a particular infection of an insect.

The invention will now be further described by way of the followingnon-limiting examples.

EXAMPLES List of Abbreviations

-   ACN acetonitrile-   AIBN azobi sisobutyronitrile-   BSA bovine serum albumin-   BOC tert-butoxycarbonyl-   BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride-   DCC N,N′-Dicyclohexylcarbodiimide solution-   DCM dichloromethane-   DEAD Diethyl azodicarboxylate-   DIEA diisopropylethylamine-   DMF N,N-dimethylformamide-   DMAP 4-(Dimethylamino)pyridine-   DMSO dimethylsulfoxide-   EDAC N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   ES electrospray-   EtOAc or EA ethyl acetate-   HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5    b]pyridinium 3-oxide hexafluorophosphate-   HOBt or HOBT 1-hydroxybenzotriazole-   KHMDS potassium hexamethyldisilazide, more precisely potassium    bis(trimethylsilyl)amide-   MeOH methanol-   PE petroleum ether-   TBAF tert-butyl ammonium fluoride-   THF tetrahydrofuran-   TLC thin-layer chromatography

Preparation Examples

The preparation examples below are non-limiting examples of methods usedto prepare the examples of the invention. The 4-fluoro-N-methyl leucinereagent protected with the tert-butyloxycarbonyl group (BOC) shown belowis used in the preparation of the starting material shown in schemes 1and 2.

This compound is prepared according to standard procedures fromcommercially-available 4-fluoroleucine (Chemical Abstracts RegistryNumber 857026-04-1). It will be appreciated that other groups R¹ to R⁴may also be prepared with different leucine analogs in a similar manner.For example, 3-fluoroleucine (Chemical Abstracts Registry No.171077-98-8, for example see Kaneko et al., Chem. Pharm Bull., 1995,43(5), 760-765) and 5-fluoroleucine (Chemical Abstracts Registry No.159415-71-1, see Moody et al., Tett. Lett., 1994, 35(30), 5485-8) arealso known and could be used to prepare compounds where R¹ to R⁴ aredifferently substituted fluoro leucine residues. In addition, it will beappreciated that alternative amino acids with different side chains mayalso used to prepare alternative compounds of the invention.

As shown in Scheme 1 above, the preparation of the compounds of theinvention is conducted by cyclization of the precursor 1-7 afterdeproctection of the terminal amine and carboxylic acid groups. It willbe appreciated by skilled persons in the art that using the generalprocess outlined in Scheme 1 a wide variety of compounds of theinvention may be prepared by selecting the appropriate monomer startingmaterials with the desired groups R¹, R², R³, R⁴, Cy¹ and Cy² in placeand preparing the dimers of general formulae 1-1, 1-2, 1-3 and 1-4 bydeprotection of the appropriate carboxylic acid and amino groups andamide formation.

Preparation Examples 1-28 shown below provide processes for thepreparation of various monomer compounds M1 to M50 substituted with awide variety of groups R¹, R², R³, R⁴, Cy¹ and Cy². In many cases, themonomers have the natural stereochemical configuration corresponding toPF1022A that enable the preparation of a diverse set of dimer compoundsused for the preparation of the compounds of the invention. Preparationof the corresponding monomer and dimer compounds in which the chiralcarbon atom has the inverted stereochemical configuration allows for thepreparation of compounds of the invention in which at least one carbonatom bearing the groups R¹, R², R³, R⁴, Cy¹ and Cy² has thestereochemical configuration described in Tables 1 to 5.

The cyclic depsipeptide compounds in the examples are named withreference to Tables 7-120 for substituents Cy¹, Cy², R¹, R², R³, R⁴,R^(a) and R^(b) present in the compounds modified by Tables 1 to 5 todepict the stereochemical configuration of the carbon atoms bearingthese groups groups. For example, the compound #10-18/1-3 refers to acyclic depsipeptide of formula (I) having the substitution pattern shownin the 18^(th) entry of Table 10 with the stereochemical configurationfor the carbon atom bearing groups Cy¹, Cy², R¹, R², R³, R⁴, R^(a) andR^(b) shown in the 3^(rd) entry of Table 1.

Preparation Example 1: Preparation of Monomer M1

Monomer M1 was prepared by the process shown in Scheme 2 below.

Experimental Details

1-Benzyl 4-methyl (2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate

Into a 20-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (150g, 606.69 mmol, 1.00 equiv) in N,N-dimethylformamide (5 L), Cs₂CO₃ (396g, 1.22 mol, 2.00 equiv), BnBr (124 g, 725.02 mmol, 1.20 equiv). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 10 L of EA. The resulting mixturewas washed with 3×5 L of H₂O. The resulting mixture was washed with 3×5L of brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 170 g (83%) of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate as a white solid. MS(ES, m/z): 338 (M+H).

1-Benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate

Into a 10 L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]butanedioate (170 g, 503.90 mmol,1.00 equiv) in N,N-dimethylformamide (5 mL), Ag₂O (348 g, 3.00 equiv),CH₃I (1433 g, 10.10 mol, 20.00 equiv). The resulting solution wasstirred for 1 h at 60° C. in an oil bath. The resulting solution wasdiluted with 10 L of EA. The resulting mixture was washed with 3×8 L ofH₂O. The resulting mixture was washed with 3×8 L of brine. The organicphase was dried over anhydrous sodium sulfate. The solids were filteredout. The resulting mixture was concentrated under vacuum. This resultedin 159 g (90%) of 1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate as yellow oil.MS (ES, m/z): 352 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid

Into a 10-L 3-necked round-bottom flask, was placed a solution of1-benzyl 4-methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]butanedioate (159 g) inmethanol (3 L), Palladium on carbon (15.9 g, 0.10 equiv), H₂ (gas)(enough). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 115 g (97%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid as yellow oil. MS (ES, m/z): 262 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid

Into a 3-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methoxy-4-oxobutanoicacid (114 g) in tetrahydrofuran (4 L), CH₃MgBr (874 mL, 6.00 equiv). Theresulting solution was stirred for 3 h at −30° C. in a cold bath. Thereaction was then quenched by the addition of 1000 mL of NH₄Cl/H₂O. ThepH value of the solution was adjusted to 3-4 with hydrogen chloride/H₂O.The resulting solution was diluted with 6 L of H₂O. The resultingsolution was extracted with 3×4 L of ethyl acetate and the organiclayers combined. The resulting mixture was washed with 2×5 L of brine.The organic phase was dried over anhydrous sodium sulfate. The solidswere filtered out. The resulting mixture was concentrated under vacuum.This resulted in 90 g (crude) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid as yellow oil. MS (ES, m/z): 262 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoate

Into a 3-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoicacid (90 g) in dichloromethane (4 L), (diazomethyl)trimethylsilane (340mL, 2.00 equiv, 2M). The resulting solution was stirred for 2 h at roomtemperature in an ice/salt bath. The resulting mixture was washed with2×3 L of H₂O. The resulting mixture was washed with 2×3 L of brine. Theorganic phase was dried over anhydrous sodium sulfate. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Thisresulted in 92 g (crude) of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoateas yellow oil. MS (ES, m/z): 276 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 3-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-hydroxy-4-methylpentanoate(90 g) in dichloromethane (3.0 L), DAST (106 g, 2.00 equiv). Theresulting solution was stirred for 2 h at −30° C. in a cold bath. Thereaction was then quenched by the addition of 1 L of NaHCO₃ at 0° C. Theresulting mixture was washed with 2×1 L of H₂O. The resulting mixturewas washed with 2×1 L of brine. The organic phase was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:100-1:20). Thisresulted in 15 g (16%) of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 278 (M+H).

(S)-2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoic acid(M1)

Into a 500 mL 3-necked round-bottom flask, was placed a solution of(S)-methyl2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoate (15 g)in MeOH (80 mL), LiOH (11.4 g, 5.00 equiv) in H₂O (150 mL). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was extracted with 3×100 mL of ethyl acetate. The pHvalue of the water layers was adjusted to 3-4 with hydrogenchloride/H₂O. The resulting solution was extracted with 3×100 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 2×5 L of brine. The organic phase was dried over anhydroussodium sulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 12.6 g (89%) of(S)-2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoic acidas yellow oil. MS (ES, m/z): 264 (M+H).

Preparation Example 2: Preparation of Monomer M2

Monomer M2 was prepared by the process shown in Scheme 3 below.

Experimental Details

(R)-2-Hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid

Into a 500-mL 3-necked round-bottom flask, was placed(R)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoic acid (20 g, 85.77mmol, 1.00 equiv), sulfuric acid (0.5 M) (340 mL). This was followed bythe addition of a solution of NaNO₂ (35.5 g, 514.49 mmol, 6.00 equiv) inwater (80 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 1 h at 0° C. The resulting solution was allowed to react,with stirring, overnight at room temperature. The solids were collectedby filtration. This resulted in 17.5 g (87%) of(R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid as a whitesolid. MS (ES, m/z): 233 (M−H); ¹H NMR (DMSO, 300 MHz) δ: 7.63 (d, J=3.9Hz, 2H), 7.46 (d, J=4.0 Hz, 2H), 4.21-4.17 (m, 1H), 3.09-3.03 (m, 1H),2.91-2.84 (m, 1H).

Benzyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (M2)

Into a 500-mL 3-necked round-bottom flask, was placed(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoic acid (17.5 g,74.73 mmol, 1.00 equiv), (bromomethyl)benzene (15.3 g, 89.46 mmol, 1.20equiv), potassium carbonate (31 g, 224.30 mmol, 3.00 equiv),N,N-dimethylformamide (100 mL). The resulting solution was stirred for30 min at 0° C. and allowed to reach room temperature with stirringovernight. The reaction was then quenched by the addition of 250 mL ofwater. The resulting solution was extracted with 3×150 mL of ethylacetate and the organic layers were combined. The resulting mixture waswashed with 3×250 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1:6)to give 10.6 g (44%) of benzyl(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate as a white solid.¹H NMR (DMSO, 300 MHz) δ: 7.60 (d, J=4.0 Hz, 2H), 7.42 (d, J=4.0 Hz,2H), 7.39-7.27 (m, 5H), 5.72 (d, J=3 Hz, 1H), 5.10 (s, 2H), 4.40-4.33(m, 1H), 3.10-3.04 (m, 1H), 2.99-2.91 (m, 1H).

Preparation Example 3: Preparation of Monomer M3

Monomer M3 was prepared by the process shown in Scheme 4 below.

Experimental Details

(2R)-3-(4-fluorophenyl)-2-hydroxypropanoic acid

Into a 500-mL 4-necked round-bottom flask, was placed(2R)-2-amino-3-(4-fluorophenyl)propanoic acid (10 g, 54.59 mmol, 1.00equiv), sulfuric acid (218.6 mL, 2.00 equiv). This was followed by theaddition of a solution of NaNO₂ (23 g, 333.33 mmol, 6.00 equiv) in water(15 mL) dropwise with stirring at 0° C. The resulting solution wasstirred for 3 h at 5° C. The resulting solution was extracted with 3×30mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 5×40 mL of sodium chloride. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 12 g (crude) of (2R)-3-(4-fluorophenyl)-2-hydroxypropanoicacid as a white solid. MS (ES, m/z): 183 (M−H).

benzyl (2R)-3-(4-fluorophenyl)-2-hydroxypropanoate (M3)

benzyl (2R)-3-(4-fluorophenyl)-2-hydroxypropanoate (M3): Into a 50-mL3-necked round-bottom flask, was placed(2R)-3-(4-fluorophenyl)-2-hydroxypropanoic acid (7 g, 38.01 mmol, 1.00equiv), N,N-dimethylformamide (30 mL), potassium carbonate (16 g, 115.77mmol, 3.00 equiv). This was followed by the addition of BnBr (7.8 g,45.61 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 30 min at 0° C. The resulting solution wasallowed to react, with stirring, for an additional 14 h at roomtemperature. The solids were filtered out. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:30). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 6 g (58%) of benzyl(2R)-3-(4-fluorophenyl)-2-hydroxypropanoate as a white solid. ¹H NMR(DMSO, 300 MHz) δ: 7.41-7.22 (m, 7H), 7.09-7.03 (m, 2H), 5.10 (s, 2H),4.31-4.27 (m, 1H), 2.99-2.93 (m, 1H), 2.88-2.81 (m, 1H).

Preparation Example 4: Preparation of Monomer M4

Monomer M4 was prepared by the process shown in Scheme 5 below.

Experimental Details

(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid

Into a 2000-mL 4-necked round-bottom flask, was placed(2R)-2-amino-3-(4-bromophenyl)propanoic acid (150 g, 614.54 mmol, 1.00equiv), sulfuric acid (0.5M/L) (2500 mL). This was followed by theaddition of a solution of NaNO₂ (256 g, 3.71 mol, 6.00 equiv) in water(900 mL) dropwise with stirring. The resulting solution was stirred for48 h at room temperature. The solids were collected by filtration. Thesolid was dried in an oven under reduced pressure. This resulted in 240g (80%) of (2R)3-(4-bromophenyl)-2-hydroxypropanoic acid as a whitesolid. MS (ES, m/z): 243 (M−H); ¹H NMR (DMSO, 300 MHz) δ: 12.59 (br s,1H), 7.51-7.44 (m, 2H), 7.27-7.14 (m, 2H), 5.34 (br s, 1H), 4.16-4.12(m, 1H), 2.97-2.91 (m, 1H), 2.80-2.70 (m, 1H).

Benzyl (2R)-3-(4-bromophenyl)-2-hydroxypropanoate

Into a 2000-mL 4-necked round-bottom flask, was placed(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (60 g, 244.83 mmol, 1.00equiv), potassium carbonate (67.6 g, 489.11 mmol, 2.00 equiv),N,N-dimethylformamide (1000 mL). This was followed by the addition ofBnBr (50.3 g, 294.10 mmol, 1.20 equiv) dropwise with stirring. Theresulting solution was stirred for 1 overnight at room temperature. Theresulting solution was diluted with 2000 mL of H₂O. The resultingsolution was extracted with 3×500 mL of ethyl acetate and the organiclayers combined. The organic layers were washed with 3×500 mL of waterand 1×500 mL of brine. The organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 62 g (76%) of benzyl(2R)-3-(4-bromophenyl)-2-hydroxypropanoate as a white solid. ¹H NMR(DMSO, 300 MHz) δ: 7.49 (d, J=3.9 Hz, 2H), 741-7.34 (m, 5H), 7.15 (d,J=4.4 Hz, 2H), 5.28-5.15 (m, 2H), 4.55-4.51 (m, 1H), 3.23-3.16 (m, 1H),3.07-3.01 (m, 1H).

Benzyl (2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate

Into a 2-L 4-necked round-bottom flask, was placed benzyl(2R)-3-(4-bromophenyl)-2-hydroxypropanoate (60 g, 179.00 mmol, 1.00equiv), N,N-dimethylformamide (1000 mL), 1H-imidazole (24.5 g, 359.89mmol, 2.00 equiv). This was followed by the addition of TBDMSC1 (32.4 g,1.20 equiv) dropwise with stirring. The resulting solution was stirredfor 16 h at room temperature. The resulting solution was diluted with 2L of H₂O. The resulting solution was extracted with 3×500 mL of ethylacetate and the organic layers combined. The organic layers were washedwith 3×500 mL of brine. The organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:50). Thisresulted in 78 g (97%) of benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate asyellow oil. MS (ES, m/z): 449 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.44 (d,J=4.2 Hz, 2H), 7.40-7.31 (m, 5H), 7.16 (d, J=4.0 Hz, 2H), 5.13 (s, 2H),4.50-4.46 (m, 1H), 3.03-2.98 (m, 1H), 2.86-2.79 (m, 1H), 0.73 (s, 9H),−0.15 (s, 3H), −0.25 (s, 3H).

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoate

Into a 2-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (78 g,173.54 mmol, 1.00 equiv), X-phos (8.27 g, 0.10 equiv), Pd(OAc)₂ (1.95 g,8.69 mmol, 0.05 equiv), toluene (1500 mL), morpholine (45.3 g, 519.97mmol, 3.00 equiv), Cs₂CO₃ (170 g, 3.00 equiv). The resulting solutionwas stirred for 16 h at 90° C. The solids were filtered out. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:5). This resulted in 64 g (81%) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoateas yellow oil. MS (ES, m/z): 456 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ:7.34-7.31 (m, 5H), 7.12 (d, J=4.2 Hz, 2H), 6.90-6.80 (m, 2H), 5.20-5.10(m, 2H), 4.36-4.32 (m, 1H), 3.90-3.80 (m, 4H), 3.13-3.05 (m, 4H),3.04-2.95 (m, 1H), 2.89-2.82 (m, 1H), 0.79 (s, 9H), −0.15 (s, 3H), −0.20(s, 3H).

Benzyl (2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (M4)

Into a 2000-mL 4-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(morpholin-4-yl)phenyl]propanoate(60 g, 131.68 mmol, 1.00 equiv), tetrahydrofuran (1200 mL). This wasfollowed by the addition of TBAF (51.7 g, 197.74 mmol, 1.20 equiv), inportions at 0° C. The resulting solution was stirred for 20 min at roomtemperature. The resulting solution was diluted with 2000 mL of H₂O. Theresulting solution was extracted with 3×500 mL of ethyl acetate and theorganic layers combined. The organic layers were washed with 3×500 mL ofwater and 1×500 mL of brine. The organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:3). This resulted in 42 g (93%) of benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate as a yellow solid.MS (ES, m/z): 342 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.40-7.27 (m, 5H),7.06 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.57 (d, J=6.3 Hz, 1H),5.08 (s, 2H), 4.27-4.21 (m, 1H), 3.75-3.71 (m, 4H), 3.06-3.03 (m, 4H),2.91-2.74 (m, 2H).

Preparation Example 5: Preparation of Monomer M5

Monomer M5 was prepared by the process shown below.

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(M5)

Into a 3000-mL round-bottom flask, was placed tetrahydrofuran (2 L),(2S)-2-[[(tert-butoxy)carbonyl]amino]-4,4-dimethylpentanoic acid (30 g,122.29 mmol, 1.00 equiv), sodium hydride (48 g, 2.00 mol, 16.35 equiv),CH₃I (348 g, 2.45 mol, 20.05 equiv). The resulting solution was stirredovernight at 35° C. The reaction was then quenched by the addition of2000 mL of water/ice. The pH value of the solution was adjusted to 4with hydrogen chloride (2 mol/L). The resulting solution was extractedwith 3×2 L of ethyl acetate and the organic layers combined and driedover anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 23 g (73%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acidas a yellow solid. MS (ES, m/z): 260 (M+H); ¹H NMR (300 MHz, CDCl₃): δ4.92-4.88 (m, 0.5H), 4.68-4.64 (m, 0.5H), 2.83-2.80 (m, 3H), 1.91-1.64(m, 2H), 1.51 (s, 9H), 0.96 (s, 9H).

Preparation Example 6: Preparation of Monomer M8

Monomer M8 was prepared by the process shown in Scheme 6 below.

Experimental Details

(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoic acid

Into a 2000-mL 3-necked round-bottom flask, was placed a solution of(2R)-2-amino-3-(4-tert-butylphenyl)propanoic acid (30 g, 135.57 mmol,1.00 equiv) in sulfuric acid (0.5M) (480 mL), a solution of NaNO₂ (94 g,1.36 mol, 10.00 equiv) in water (180 mL). The resulting solution wasstirred overnight at room temperature in an ice/salt bath. The solidswere collected by filtration. This resulted in 20.0 g (66%) of(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoic acid as a white solid. MS(ES, m/z): 221 (M−H).

(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (M8)

Into a 2000-mL 3-necked round-bottom flask, was placed a solution of(2R)3-(4-tert-butylphenyl)-2-hydroxypropanoic acid (40 g, 179.95 mmol,1.00 equiv) in N,N-dimethylformamide (1000 mL), potassium carbonate (50g, 361.77 mmol, 2.00 equiv), BnBr (61 g, 356.66 mmol, 2.00 equiv). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 2000 mL of EA. The resulting mixturewas washed with 3×2000 mL of water. The resulting mixture was washedwith 2×2000 mL of brine. The mixture was dried over anhydrous sodiumsulfate. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:50-1:10). This resulted in42 g (75%) of benzyl (2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate asyellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.27 (m, 7H), 7.10 (d, J=8.1Hz, 2H), 5.20 (s, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.14-2.93 (m, 2H), 1.31(s, 9H).

Preparation Example 7: Preparation of Monomer M9

Monomer M9 was prepared by the process shown in Scheme 7 below.

Experimental Details

(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acid

Into a 1000-mL 3-necked round-bottom flask, was placed(2R)2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride(10 g, 35.01 mmol, 1.00 equiv). This was followed by the addition of asolution of NaNO₂ (29 g, 420.29 mmol, 12.00 equiv) in water (150 mL)dropwise with stirring at 0° C. To this was added sulfuric acid (0.5M/L)(300 mL). The resulting solution was stirred overnight at roomtemperature. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 11 g(crude) of (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acidas yellow oil. MS (ES, m/z): 249 (M−H).

Benzyl (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (M9)

Into a 1000-mL 3-necked round-bottom flask, was placed(2R)2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoic acid (11 g, 43.97mmol, 1.00 equiv), N,N-dimethylformamide (300 mL), potassium carbonate(12 g, 86.82 mmol, 2.00 equiv). This was followed by the addition of(bromomethyl)benzene (9 g, 52.62 mmol, 1.20 equiv) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of 100 mL ofwater. The resulting solution was extracted with 3×150 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum.

This resulted in 7.6 g (51%) of benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate as yellow oil.¹H NMR (DMSO, 300 MHz) δ: 7.45-7.30 (m, 7H), 7.25-7.17 (m, 2H), 5.70 (d,J=2.7 Hz, 1H), 5.10 (s, 2H), 4.34-4.32 (m, 1H), 3.04-2.98 (m, 1H),2.92-2.85 (m, 1H).

Preparation Example 8: Preparation of Monomer M10

Monomer M10 was prepared by the process shown in Scheme 8 below.

Experimental Details

4-(5-bromopyridin-2-yl)morpholine

Into a 1-L round-bottom flask, was placed a solution of5-bromo-2-chloropyridine (50 g, 259.82 mmol, 1.00 equiv) inN,N-dimethylformamide (300 mL), morpholine (91 g, 1.04 mol, 4.00 equiv),potassium carbonate (108 g, 781.42 mmol, 3.00 equiv). The resultingsolution was stirred overnight at 120° C. The resulting solution wasextracted with 5×150 mL of ethyl acetate and the organic layers werecombined. The resulting mixture was washed with 3×100 mL of brine. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The resulting mixture was washed with PE:EA=1:5. This resultedin 80 g (63%) of 4-(5-bromopyridin-2-yl)morpholine as a white solid. MS(ES, m/z): 243 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.22 (s, 1H), 7.57 (d,J=4.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 3.82 (t, J=5.1 Hz, 4H), 3.48 (t,J=5.1 Hz, 4H).

methyl (2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate

Into a 250-mL round-bottom flask and maintained with an inert atmosphereof nitrogen, was placed a solution of 4-(5-bromopyridin-2-yl)morpholine(5 g, 20.57 mmol, 1.00 equiv) in N,N-dimethylformamide (120 mL), methylprop-2-enoate (3.54 g, 41.12 mmol, 2.00 equiv), Pd(OAc)₂ (92 mg, 0.41mmol, 0.02 equiv), sodium bicarbonate (3.46 g, 41.19 mmol, 2.00 equiv),Bu₄NCl (11.4 g, 41.02 mmol, 2.00 equiv). The resulting solution wasstirred for 3 days at 100° C. The resulting solution was extracted with5×150 mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 3×100 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The solids werefiltered out. This resulted in 11.5 g (56%) of methyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate as a light brownsolid. MS (ES, m/z): 249 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.30 (s, 1H),7.72-7.58 (m, 2H), 6.64 (d, J=4.5 Hz, 1H), 6.27 (d, J=8.0 Hz, 1H),3.84-3.80 (m, 7H), 3.62 (t, J=4.8 Hz, 4H).

(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid

Into a 500-mL round-bottom flask, was placed a solution of methyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate (11 g, 44.31 mmol,1.00 equiv) in methanol/H₂O (60:60 mL), LiOH (10.6 g, 442.59 mmol, 10.00equiv). The resulting solution was stirred for 1 h at 80° C. Theresulting solution was diluted with 150 ml of water. The pH value of thesolution was adjusted to 6-7 with NaHCO₃(Sat.). The resulting solutionwas extracted with 5×150 mL of ethyl acetate and the organic layerscombined.

The organic phase was washed with 3×150 mL of brine. The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 10.4 g (crude) of(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid as a lightbrown solid. MS (ES, m/z): 245 (M+H).

benzyl (2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate

Into a 250-mL round-bottom flask, was placed a solution of(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoic acid (4 g, 17.08mmol, 1.00 equiv) in N,N-dimethylformamide (70 mL), potassium carbonate(7.1 g, 51.37 mmol, 3.00 equiv), (bromomethyl)benzene (4.4 g, 25.73mmol, 1.50 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting solution was extracted with 5×150 mL of ethylacetate and the organic layers were combined. The resulting mixture waswashed with 3×150 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The resulting mixture waswashed with 1×70 mL of PE. The solids were collected by filtration. Thisresulted in 10 g (72%) of benzyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate as a yellow solid.MS (ES, m/z): 325 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.30 (s, 1H),7.70-7.62 (m, 2H), 7.45-7.32 (m, 5H), 6.63 (d, J=4.5 Hz, 1H), 6.32 (d,J=8.0 Hz, 1H), 5.25 (s, 2H), 3.82 (t, J=4.5 Hz, 4H), 3.63-3.60 (m, 4H).

(2R, 3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate

Into a 100-mL 3-necked round-bottom flask, was placed tert-Butanol:H₂O(20:20 mL), AD-mix-α (8.6 g), This was followed by addition of benzyl(2E)-3-[6-(morpholin-4-yl)pyridin-3-yl]prop-2-enoate (2 g, 6.17 mmol,1.00 equiv) and MeSO₂NH₂ (586 g, 6.17 mol, 1.00 equiv) with stirring at0° C. The resulting solution was stirred for 3 days at room temperature.The reaction was then quenched by the addition of Na₂SO₃. The resultingsolution was extracted with 3×150 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:1). This resulted in 5.4 g (49%) ofbenzyl (2R,3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate as alight yellow solid. MS (ES, m/z): 359 (M+H).

benzyl (2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (M10)

Into a 100-mL round-bottom flask, was placed a solution of benzyl (2R,3S)-2,3-dihydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (1.5 g,4.19 mmol, 1.00 equiv) in dichloromethane (15 mL), trifluoroacetic acid(5 mL), Et₃SiH (10 mL). The resulting solution was stirred for 3 days at50° C. The resulting mixture was concentrated under vacuum. The reactionwas then quenched by the addition of water/ice. The pH value of thesolution was adjusted to 9 with sodium bicarbonate aq. The resultingsolution was extracted with 3×40 mL of dichloromethane and the organiclayers were combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:2). This resulted in 2.3 g(27%) of benzyl(2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate as yellowoil. MS (ES, m/z): 343 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.02 (s, 1H),7.43-7.32 (m, 6H), 6.54 (d, J=4.4 Hz, 1H), 5.21 (s, 2H), 4.52-4.46 (m,1H), 3.84 (t, J=7.8 Hz, 4H), 3.48 (t, J=4.8 Hz, 4H) 3.05-3.01 (m, 1H),2.91-2.85 (m, 1H).

Preparation Example 9: Preparation of Monomer M11

Monomer M11 was prepared by the process shown in Scheme 9 below.

Experimental Details

(2R)-3-(4-cyanophenyl)-2-hydroxypropanoic acid

Into a 500-mL 3-necked round-bottom flask, was placed(2R)2-amino-3-(4-cyanophenyl)propanoic acid (10 g, 52.58 mmol, 1.00equiv), 0.5M sulfuric acid (100 mL). This was followed by the additionof a solution of NaNO₂ (21.8 g, 315.94 mmol, 5.98 equiv) in water (20mL) dropwise with stirring at 0° C. The resulting solution was stirredfor 18 h at room temperature. The resulting solution was extracted with2×500 mL of ethyl acetate and the organic layers combined. The organicmixture was washed with 2×500 mL of brine and dried over anhydroussodium sulfate. The solids were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 9 g (crude) of(2R)-3-(4-cyanophenyl)-2-hydroxypropanoic acid as a light yellow liquid.MS (ES, m/z): 190 (M−H).

benzyl (2R)-3-(4-cyanophenyl)-2-hydroxypropanoate (M11)

Into a 250-mL round-bottom flask, was placed(2R)3-(4-cyanophenyl)-2-hydroxypropanoic acid (9 g, 47.08 mmol, 1.00equiv), N,N-dimethylformamide (150 mL). This was followed by theaddition of potassium carbonate (20.6 g, 149.05 mmol, 3.17 equiv), inportions at 0° C. To this was added BnBr (16.9 g, 98.81 mmol, 2.10equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 16 h at room temperature. The resulting solution was dilutedwith 50 mL of water and extracted with 2×200 mL of ethyl acetate. Theorganic layers combined. The combined mixture was washed with 3×150 mLof aq. NaCl and dried over anhydrous sodium sulfate. The solids werefiltered out.

The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1/10-1/5). Thisresulted in 2.5 g (19%) of benzyl(2R)-3-(4-cyanophenyl)-2-hydroxypropanoate as a light yellow liquid. ¹HNMR (CDCl₃, 300 MHz) δ: 7.50 (d, J=4.0 Hz, 2H), 7.43-7.32 (m, 5H), 7.23(d, J=4.0 Hz, 2H), 5.31-5.13 (m, 2H), 4.53-4.49 (m, 1H), 3.21-3.15 (m,1H), 3.06-2.99 (m, 1H).

Preparation Example 10: Preparation of Monomer M16

Monomer M16 was prepared by the process shown in Scheme 10 below.

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (14.53g, 32.33 mmol, 1.00 equiv), 4,4-difluoropiperidine (6.2 g, 51.19 mmol,1.20 equiv), Cs₂CO₃ (19 g, 3.00 equiv), X-PhOS (309 mg, 0.02 equiv),Toluene (50 mL), Pd(OAc)₂ (145 mg, 0.65 mmol, 0.02 equiv). The resultingsolution was stirred for 16 h at 90° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:6). This resulted in 12.28g (78%) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoateas coroless oil.

Benzyl (2R)-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]-2-hydroxypropanoate(M16)

Into a 100-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]propanoate(12.28 g, 25.08 mmol, 1.00 equiv), tetrahydrofuran (30 mL), TBAF (8.4 g,32.13 mmol, 1.20 equiv). The resulting solution was stirred for 20 minat room temperature. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with 100 mL of ethyl acetate.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 6.8 g (72%) of benzyl(2R)-3-[4-(4,4-difluoropiperidin-1-yl)phenyl]-2-hydroxypropanoate as awhite solid. MS (ES, m/z): 376 (M+H).

Preparation Example 11: Preparation of Monomer M17

Monomer M17 was prepared by the process shown in Scheme 11 below.

Experimental Details

benzyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-4,4,4-trifluorobutanoate

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (15mL), 2-[[(tert-butoxy)carbonyl]amino]-4,4,4-trifluorobutanoic acid (1.5g, 5.83 mmol, 1.00 equiv), Cs₂CO₃ (5.7 g, 17.49 mmol, 3.00 equiv), BnBr(1.1 g, 6.43 mmol, 1.10 equiv). The resulting solution was stirred for 4h at room temperature. The resulting solution was diluted with 20 mL ofwater, extracted with 3×30 mL of ethyl acetate and the organic layerscombined. The organic layers were washed with 1×40 mL of brine. Theorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:20). This resulted in 1.3 g (64%) ofbenzyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-4,4,4-trifluorobutanoate asa white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.40-7.34 (m, 5H), 5.25 (s,2H), 4.60-4.59 (m, 1H), 2.78-2.71 (m, 2H), 1.45 (s, 9H).

benzyl-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4,4-trifluorobutanoate

Into a 250-mL round-bottom flask, was placed N,N-dimethylformamide (25mL), benzyl-2-[[(tert-butoxy)carbonyl]amino]-4,4,4-trifluorobutanoate(3.1 g, 8.93 mmol, 1.00 equiv), Ag₂O (5.4 g), CH₃I (17 g, 119.77 mmol,13.42 equiv). The resulting solution was stirred for 2 h at 60° C. Thesolids were filtered out. The filtrate was diluted with 80 mL of water,extracted with 3×50 mL of ethyl acetate and the organic layers combined.The organic layers were washed with 1×20 mL of brine. The organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 2.8 g (87%) ofbenzyl-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4,4-trifluorobutanoateas yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.38-7.35 (m, 5H), 5.26-5.20(m, 2H), 4.47-4.44 (m, 1H), 2.96-2.89 (m, 3H), 2.79-2.63 (m, 2H),1.47-1.41 (m, 9H).

2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4,4-trifluorobutanoic acid(M17)

Into a 100-mL round-bottom flask, was placed ethyl acetate (20 mL),benzyl-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4,4-trifluorobutanoate(3.1 g, 8.58 mmol, 1.00 equiv), Palladium on carbon (300 mg), to theabove hydrogen was introduced. The resulting solution was stirred for 1h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 2.1 g (90%) of2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4,4-trifluorobutanoic acid asyellow oil.

Preparation Example 12: Preparation of Monomer M19

Monomer M19 was prepared by the process shown in Scheme 12 below.

Experimental Details

tert-butyl (2S)-2-[(diphenylmethylidene)amino]-4-methylpent-4-enoate

Into a 500-mL 3-necked round-bottom flask, was placed tert-butyl2-[(diphenylmethylidene)amino]acetate (15 g, 50.78 mmol, 1.00 equiv),1-bromopropan-2-one (8.2 g, 59.86 mmol, 1.20 equiv), toluene (150 mL),chloromethane (65 mL). This was followed by the addition ofCAS:200132-54-3 (1.57 g, 2.59 mmol, 0.05 equiv), in portions at −20° C.To this was added a solution of potassium hydroxide (28.6 g, 510.71mmol, 10.00 equiv) in water (30 mL) dropwise with stirring at −20° C.The resulting solution was stirred for 48 h at −20° C. The solids werefiltered out. The filtrate was washed by water (50 mL×3) and brine (50mL×1). The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude product was purified bychromatography with the following conditions (IntelFlash-1): Column, C18silica gel; mobile phase, CH₃CN/H₂O (0.5% NH₃H₂O); Detector, UV 254 nm.This resulted in 12.0 g (68%) of tert-butyl(2S)-2-[(diphenylmethylidene)amino]-4-methylpent-4-enoate as a whitesolid. MS (ES, m/z): 350 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 7.64-7.61 (m,2H), 7.45-7.28 (m, 6H), 7.19-7.16 (m, 2H), 4.74-4.72 (m, 2H), 4.10-4.06(m, 1H), 2.62-2.57 (m, 2H), 1.52 (s, 3H), 1.45 (s, 9H).

tert-butyl (2S)-2-amino-4-methylpent-4-enoate

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl(2S)-2-[(diphenylmethylidene)amino]-4-methylpent-4-enoate (10 g, 28.62mmol, 1.00 equiv) in 2N HCl (100 mL). The resulting solution was stirredfor 1 h at room temperature. The resulting solution was extracted with3×30 mL of n-hexane and the aqueous layer combined. The pH value of theaqueous phase was adjusted to 9 with NaHCO₃(Sat.). The resultingsolution was extracted with 4×30 mL of ethyl acetate and the organiclayers combined. The organic phase was washed with 3×30 mL of brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 4.2 g (79%) of tert-butyl(2S)-2-amino-4-methylpent-4-enoate as light yellow oil. MS (ES, m/z):186 (M+H).

(2S)-2-amino-4-methylpent-4-enoic acid

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl(2S)-2-amino-4-methylpent-4-enoate (4.2 g, 22.67 mmol, 1.00 equiv) indichloromethane (20 mL), trifluoroacetic acid (10 mL). The resultingsolution was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. This resulted in 3 g (crude) of(2S)-2-amino-4-methylpent-4-enoic acid as brown oil. MS (ES, m/z): 128(M−H).

(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoic acid

Into a 250-mL round-bottom flask, was placed a solution of(2S)-2-amino-4-methylpent-4-enoic acid (3 g, 23.23 mmol, 1.00 equiv) indioxane (100 mL), (Boc)₂O (7.5 g, 34.36 mmol, 1.50 equiv), a solution ofsodium hydroxide (3 g, 75.00 mmol, 3.00 equiv) in water (5 mL). Theresulting solution was stirred for 1 h at room temperature. Theresulting solution was extracted with 2×20 mL of n-hexane and theaqueous phase combined. The pH value of the aqueous phase was adjustedto 6-5 with HCl (2N.). The resulting solution was extracted with 3×30 mLof ethyl acetate and the organic layers combined. The organic phase waswashed with 3×30 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 3.5 g(66%) of (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoic acidas light yellow oil. MS (ES, m/z): 228 (M−H).

benzyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoate

Into a 250-mL round-bottom flask, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoic acid (3.5 g,15.27 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL), BnBr (3.2 g,18.71 mmol, 1.20 equiv), potassium carbonate (6.3 g, 45.58 mmol, 3.00equiv). The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of water(100 ml). The resulting solution was extracted with 3×40 mL of ethylacetate and the organic layers combined. The organic phase was washedwith 3×30 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 4 g (82%) of benzyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoate as lightyellow oil. MS (ES, m/z): 320 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ:7.39-7.33 (m, 5H), 5.23-5.12 (m, 2H), 4.96-4.94 (m, 1H), 4.80 (d, J=14.0Hz, 2H), 4.47-4.46 (m, 1H), 2.58-2.51 (m, 1H), 2.42-2.35 (m, 1H), 1.73(s, 3H), 1.27 (s, 9H).

benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpent-4-enoate

Into a 250-mL round-bottom flask, was placed a solution of benzyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpent-4-enoate (5.2 g,16.28 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), Ag₂O (11.2 g,3.00 equiv), AcOH (1 g, 16.65 mmol, 1.00 equiv)., CH₃I (23 g, 162.04mmol, 10.00 equiv). The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The filtrate was diluted withwater (200 mL) and extracted with 3×70 mL of ethyl acetate and theorganic layers combined. The organic phase was washed with 2×50 mL ofbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 4 g(74%) of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpent-4-enoate aslight yellow oil. MS (ES, m/z): 334 (M+H); 1H NMR (CDCl₃, 300 MHz) δ:7.36 (s, 5H), 5.23 (s, 2H), 5.13-5.06 (m, 0.5H), 4.83-4.73 (m, 2.5H),2.83-2.77 (m, 3H), 2.66-2.46 (m, 2H), 1.78 (s, 3H), 1.47-1.33 (m, 9H).

benzyl (2s)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-oxopentanoate

into a 100-ml round-bottom flask, was placed a solution of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpent-4-enoate (4g, 12.00 mmol, 1.00 equiv) in CH₃CN:H₂O:EA (mL), RuCl₃ (124 mg, 0.05equiv), NaIO₄ (10.3 g, 4.00 equiv). The resulting solution was stirredfor 1 h at room temperature. The resulting solution was extracted with3×60 mL of ethyl acetate and the organic layers combined. The organicphase was washed with 3×30 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 3 g (75%) of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-oxopentanoate as lightbrown oil. MS (ES, m/z): 336 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 7.35 (s,5H), 5.20-5.10 (m, 2H), 4.70-4.66 (m, 1H), 2.94-2.74 (m, 5H), 2.24-2.22(m, 3H), 1.49-1.31 (m, 9H).

benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-difluoropentanoate

Into a 30-mL vial, was placed a solution of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-oxopentanoate (500 mg,1.49 mmol, 1.00 equiv), dichloromethane (3 mL), methanol (0.01 mL). Thiswas followed by the addition of DAST (1.5 mL) dropwise with stirring at0° C. The resulting solution was stirred overnight at room temperature.The reaction was then quenched by the addition of water/ice. The pHvalue of the solution was adjusted to 9 with NaHCO₃(sat.). The resultingsolution was extracted with 3×50 mL of dichloromethane and the organiclayers combined The organic phase was washed with 3×30 mL of brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 1.8 g (42%) of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-difluoropentanoate asyellow oil. MS (ES, m/z): 338 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.37-7.33(m, 5H), 5.20-5.09 (m, 2H), 4.82-4.59 (m, 1H), 2.77-2.76 (m, 3H),2.57-2.47 (m, 2H), 1.72-1.57 (m, 3H), 1.41-1.30 (m, 9H).

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-difluoropentanoic acid(M19)

Into a 100-mL round-bottom flask, was placed a solution of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-difluoropentanoate(900 mg, 2.52 mmol, 1.00 equiv) in methanol (20 mL), Palladium on carbon(50 mg). To the above hydrogen was introduced. The resulting solutionwas stirred for 30 min at room temperature. The solids were filteredout. The filtrate was concentrated under vacuum. This resulted in 700 mg(crude) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-difluoropentanoic acidas a white solid. MS (ES, m/z): 268 (M+H).

Preparation Example 13: Preparation of Monomer M20

Monomer M20 was prepared by the process shown in Scheme 13 below.

Experimental Details

tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate

Into a 2-L round-bottom flask, was placed(2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoic acid (50 g,209.01 mmol, 1.00 equiv), acetonitrile (400 mL), potassium potassiummethaneperoxoate (180 g, 1.29 mol, 6.50 equiv), benzyltriethylazaniumchloride (47 g, 206.35 mmol, 1.00 equiv). The resulting solution wasstirred for 5 h at r.t. Then 2-bromo-2-methylpropane (250 mL, 10.20equiv) was added. The resulting solution was stirred overnight at 50° C.in an oil bath. The reaction mixture was cooled. The resulting mixturewas concentrated under vacuum. The residue was dissolved in 1.5 L ofethyl acetate. The resulting mixture was washed with 1×500 mL of H₂O.The organic layer was washed with 2×400 mL of brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 39 g (63%) of tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate as a whitesolid. MS (ES, m/z): 296 (M+H).

tert-butyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-iodopropanoate

Into a 250-mL round-bottom flask, was placed N,N-dimethylformamide (150mL), tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate(20 g, 67.72 mmol, 1.00 equiv). This was followed by the addition ofmethyltriphenoxyphosphonium iodide (43 g, 95.09 mmol, 1.30 equiv) inportions with stirring at 0° C. The resulting solution was stirred for 2h at room temperature. The reaction mixture was cooled to 0° C. with awater/ice bath. The reaction was then quenched by the addition of 30 gof sodium bicarbonate. The resulting solution was diluted with 260 mL ofH₂O. The resulting solution was extracted with 3×300 mL of ethyl acetateand the organic layers combined. The organic layers were washed with2×200 mL of aqueous sodium hydroxide (0.05 mol/L). The organic layerswere washed with 1×200 mL of brine. The organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:100-1:30). This resulted in 20 g (73%) of tert-butyl(2R)2-[[(benzyloxy)carbonyl]amino]-3-iodopropanoate as colorless oil. MS(ES, m/z): 406 (M+H).

tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluoro-4-hydroxy-4(trifluoromethyl)pentanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed N,N-dimethylformamide (50 mL), zinc(16 g, 244.61 mmol, 5.00 equiv), diiodane (1.25 g, 4.92 mmol, 0.10equiv), the mixture was stirred then the reaction mixture turnedcolorless, tert-butyl(2R)2-[[(benzyloxy)carbonyl]amino]-3-iodopropanoate (20 g, 49.35 mmol,1.00 equiv) and 12 (1.25 g, 4.92 mmol, 0.10 equiv) was added to reactionmixture. This was followed by the addition of a solution ofhexafluoropropan-2-one (100 mL, 3.00 equiv) in N,N-dimethylformamide (50mL) at −30° C. The resulting solution was stirred for 4 h at roomtemperature. The resulting solution was diluted with 500 mL ofice-water. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined. The organic layers were washedwith 3×100 mL of brine. The organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The crude product waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/H₂O=30%increasing to CH₃CN/H₂O=65% within 20 min; Detector, UV 220 nm. Thisresulted in 17 g (77%) of tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)pentanoateas a white solid. MS (ES, m/z): 446 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.52-7.3 (m, 5H), 6.15-5.80 (br, 1H), 5.16 (s, 2H), 4.52-4.40 (m, 1H),2.80-2.70 (m, 1H), 2.40-2.25 (m, 1H), 1.50 (s, 9H).

of tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluoro-4(trifluoromethyl)pentanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed Tol (50 mL), tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)pentanoate(12.34 g, 27.71 mmol, 1.00 equiv), phenyl 2-chloro-2-oxoacetate (7.4 g,40.09 mmol, 1.45 equiv). This was followed by the addition of pyridine(3 g, 37.93 mmol, 1.40 equiv) dropwise with stirring at 0° C. for 1hour. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. To this was added AIBN (1.8 g, 10.96 mmol,0.40 equiv) and the crude product to Tributyltin hydride (14.4 g, 49.65mmol, 1.80 equiv) and toluene at 100° C. in an oil bath. The resultingsolution was stirred for 1 h at 100° C. in an oil bath. The reactionmixture was cooled. The resulting solution was diluted with 100 mL ofether. The reaction was then quenched by the addition of 30 g ofKF/Al₂O₃. the reaction mixture was stirred at room temperature for 1hour. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:100-1:30). The crudeproduct was purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN/H₂O=40%increasing to CH3CN/H₂O=78% within 20 min; Detector, UV 254 nm. Thisresulted in 1.2 g (10%) of tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoateas a white solid. MS (ES, m/z): 430 (M+H); ¹H NMR: (300 MHz, CDCl₃,ppm): 7.46-7.31 (m, 5H), 5.46-5.30 (br, 1H), 5.15 (s, 2H), 4.50-4.30 (m,1H), 3.40-3.20 (m, 1H), 2.45-2.00 (m, 2H), 1.49 (s, 9H).

tert-butyl (2S)-2-amino-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate

Into a 100-mL round-bottom flask, was placed Palladium on carbon (400mg), methanol (40 mL), tert-butyl(2S)-2-[[(benzyloxy)carbonyl]amino]-5,5,5-trifluortrifluoromethyl)pentanoate (2.1 g, 4.89 mmol, 1.00 equiv), to the abovehydrogen was introduced. The resulting solution was stirred overnight atroom temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. This resulted in 1.4 g (97%) oftert-butyl (2S)-2-amino-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate ascolorless oil. MS (ES, m/z): 296 (M+H).

tert-butyl(2S)-2-[benzyl(methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate

Into a 250-mL round-bottom flask, was placed tetrahydrofuran (40 mL),tert-butyl (2S)-2-amino-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate(1.35 g, 4.57 mmol, 1.00 equiv). This was followed by the addition ofbenzaldehyde (1.17 g, 11.03 mmol, 2.50 equiv) dropwise at 0° C. Theresulting solution was stirred for 2 hour at room temperature. To thiswas added NaBH3CN (820 mg, 13.23 mmol, 3.00 equiv) in portions at 0° C.The resulting solution was stirred for 2 hour at room temperature. Tothe mixture was added formaldehyde (330 mg, 10.99 mmol, 2.50 equiv) inportions at 0° C. To this was added NaBH₃CN (820 mg, 13.23 mmol, 3.00equiv) in portions at 0° C. The resulting solution was stirred overnightat room temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was purified by preparativeTLC (ether:n-hexane=1:1). This resulted in 800 mg (44%) of tert-butyl(2S)-2-[benzyl(methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoateas colorless oil. MS (ES, m/z): 400 (M+H).

tert-butyl(2S)-5,5,5-trifluoro-2-(methylamino)-4-(trifluoromethyl)pentanoate

Into a 50-mL round-bottom flask, was placed tert-butyl(2S)-2-[benzyl(methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate(240 mg, 0.60 mmol, 1.00 equiv), ethyl acetate (10 mL), Palladium oncarbon (50 mg). To the above H2 (gas) was introduced. The resultingsolution was stirred for 3 h at room temperature. This resulted in 130mg (70%) of tert-butyl(2S)-5,5,5-trifluoro-2-(methylamino)-4-(trifluoromethyl)pentanoate ascolorless oil. MS (ES, m/z): 310 (M+H).

tert-butyl(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4(trifluoromethyl)pentanoate

Into a 8-mL round-bottom flask, was placed dioxane (2 mL), water (1drop), tert-butyl(2S)-5,5,5-trifluoro-2-(methylamino)-4-(trifluoromethyl)pentanoate (130mg, 0.42 mmol, 1.00 equiv), NaHCO₃(43 mg, 0.51 mmol, 1.20 equiv),9H-fluoren-9-ylmethyl chloroformate (120 mg, 0.46 mmol, 1.10 equiv). Theresulting solution was stirred for 3 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by preparative TLC (EtOAc:PE=1:5). This resulted in 150 mg(67%) of tert-butyl(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate as colorless oil. MS (ES, m/z): 554 (M+Na).

(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4(trifluoromethyl)pentanoic acid (M20)

Into a 50-mL round-bottom flask, was placed dichloromethane (10 mL),tert-butyl (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate (150 mg, 0.28 mmol,1.00 equiv). This was followed by the addition of trifluoroacetic acid(3 mL) dropwise with stirring. The resulting solution was stirred for 4h at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 210 mg of(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoicacid as colorless oil. MS (ES, m/z): 476 (M+H); ¹H NMR: (300 MHz, CDCl₃,ppm): 7.82-7.78 (m, 2H), 7.63-7.50 (m, 2H), 7.47-7.30 (m, 4H), 4.82-4.30(m, 5H), 2.90-2.78 (m, 3H), 2.60-2.20 (m, 2H).

Preparation Example 14: Preparation of Monomer M21

Monomer M21 was prepared by the process shown in Scheme 14 below.

Experimental Details

4-(4-Bromo-2-fluorophenyl)morpholine

Into a 1-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-bromo-2-fluoro-1-iodobenzene (15 g, 49.85 mmol, 1.00 equiv) in toluene(300 mL). Pd₂(dba)₃ (1.3 g, 1.42 mmol, 0.03 equiv). Cs₂CO₃ (41 g, 125.45mmol, 2.50 equiv). XantPhos (2.9 g, 5.01 mmol, 0.10 equiv). morpholine(4.3 g, 49.36 mmol, 1.00 equiv). The resulting solution was stirredovernight at 100° C. The reaction was then quenched by the addition of150 mL of water. The resulting solution was extracted with 3×100 mL ofethyl acetate and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:15). Thisresulted in 10.5 g (81%) of 4-(4-bromo-2-fluorophenyl)morpholine as ayellow solid. MS (ES, m/z): 260 (M+H).

Benzyl (2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 4-(4-bromo-2-fluorophenyl)morpholine(1.25 g, 4.81 mmol, 1.00 equiv). Pd(OAc)₂ (50 mg, 0.22 mmol, 0.05equiv). a solution of sodium bicarbonate (810 mg, 9.64 mmol, 2.00 equiv)in N,N-dimethylformamide (30 mL). Bu₄NCl (2.7 g, 9.72 mmol, 2.00 equiv).benzyl prop-2-enoate (1.6 g, 9.87 mmol, 2.00 equiv). The resultingsolution was stirred for 36 h at 100° C. The reaction was then quenchedby the addition of water. The resulting solution was extracted with4×100 mL of ethyl acetate and the organic layers combined. The organicphase was washed with 3×60 mL of brine. The organic phase was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:5). This resulted in 10.5 g (80%) of benzyl(2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate as a yellowsolid. MS (ES, m/z): 342 (M+H).

Benzyl (2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate

Into a 250-mL 3-necked round-bottom flask, was placed a solution ofAD-mix-α (12.3 g) in tert-Butanol/H₂O (60:60 mL). This was followed bythe addition of benzyl(2E)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]prop-2-enoate (3 g, 8.79 mmol,1.00 equiv), in portions at 0° C. To this was added MeSO₂NH₂ (1.23 g,1.00 equiv), in portions at 0° C. The resulting solution was stirred for3 days at room temperature. The reaction was then quenched by theaddition of Na₂SO₃. The resulting solution was extracted with 3×100 mLof ethyl acetate and the organic layers combined. The organic phase waswashed with 3×60 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 9.5 g (72%) of benzyl (2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate asyellow oil. MS (ES, m/z): 376 (M+H).

Benzyl (2R)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-hydroxypropanoate(M21)

Into a 40-mL vial, was placed a solution of benzyl (2R,3S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2,3-dihydroxypropanoate (900mg, 2.40 mmol, 1.00 equiv) in dichloromethane (2 mL), Et₃SiH (4 mL),trifluoroacetic acid (2 mL). The resulting solution was stirred for 3days at room temperature. The reaction was then quenched by the additionof water/ice. The resulting solution was extracted with 3×80 mL of ethylacetate and the organic layers combined. The organic phase was washedwith 3×60 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 4.1 g (48%) of benzyl(2R)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-hydroxypropanoate asreddish oil. MS (ES, m/z): 360 (M+H).

Preparation Example 15: Preparation of Monomer M24

Monomer M24 was prepared by the process shown in Scheme 15 below.

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4-fluorophenyl)phenyl]propanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed (4-fluorophenyl)boronic acid (1 g,7.15 mmol, 1.50 equiv), dioxane (20 mL), water (2 mL), benzyl(2R)3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (2 g,4.45 mmol, 1.00 equiv), sodium carbonate (1.2 g, 11.32 mmol, 2.50equiv), Pd(PPh3)4 (250 mg, 0.22 mmol, 0.05 equiv). The resultingsolution was stirred for 3 h at 70° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with petroleum ether. This resulted in 2.1 g (crude) of benzyl(2R)2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4-fluorophenyl)phenyl]propanoateas colorless oil. ¹H NMR (DMSO, 300 MHz) δ: 7.70-7.54 (m, 4H), 7.45 (d,J=4.2 Hz, 1H), 7.39-7.25 (m, 8H), 7.16 (d, J=4.2 Hz, 1H), 5.14 (s, 2H),4.53-4.47 (m, 1H), 3.06-2.86 (m, 2H), 0.73 (s, 9H), −0.13 (s, 3H), −0.23(s, 3H).

Benzyl (2R)-3-[4-(4-fluorophenyl)phenyl]-2-hydroxypropanoate (M24)

(2R)2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4-fluorophenyl)phenyl]propanoate(2.1 g, 4.52 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This wasfollowed by the addition of TBAF (1.5 g, 5.74 mmol, 1.30 equiv) inportions at 0° C. The resulting solution was stirred for 40 min at roomtemperature. The reaction was then quenched by the addition ofwater/ice. The resulting solution was extracted with 3×60 mL of ethylacetate and the organic layers combined. The organic phase was washedwith 3×50 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 1.2 g (76%) of benzyl(2R)3-[4-(4-fluorophenyl)phenyl]-2-hydroxypropanoate as a white crudesolid. ¹H NMR (CDCl₃, 300 MHz) δ: 7.56-7.51 (m, 2H), 7.46-7.32 (m, 7H),7.25-7.22 (m, 2H), 7.17-7.11 (m, 2H), 5.27-5.15 (m, 2H), 4.53-4.47 (m,1H), 3.12-2.92 (m, 2H).

Preparation Example 16: Preparation of Monomer M25

Monomer M25 was prepared by the process shown in Scheme 16 below.

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-dimethylcyclohex-1-en-1yl)phenyl]propanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2R)3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (1.58g, 3.52 mmol, 1.00 equiv),2-(4,4-dimethylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1 g, 4.23 mmol, 1.20 equiv), K₃PO₄ (1.86 g, 8.76 mmol, 2.50 equiv),Pd(dppf)2Cl2 (130 mg, 0.18 mmol, 0.05 equiv), dioxane (25 mL), water(2.5 mL). The resulting solution was stirred for 2 h at 75° C. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:50). This resulted in 1.5 g (89%) of benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]propanoateas yellow oil. ¹H NMR (DMSO, 300 MHz) δ: 7.40-7.28 (m, 7H), 7.17 (d,J=4.0 Hz, 2H), 6.07 (t, J=3.9 Hz, 1H), 5.23-5.13 (m, 2H), 4.44-4.40 (m,1H), 3.13-3.08 (m, 1H), 2.98-2.91 (m, 1H), 2.47-2.42 (m, 2H), 2.04-2.03(m, 2H), 1.57 (t, J=6.1 Hz, 2H), 1.01 (s, 6H), 0.85 (s, 9H), −0.07 (s,3H), −0.15 (s, 3H).

Benzyl(2R)-3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate(M25)

Into a 100-mL 3-necked round-bottom flask, was placed benzyl(2R)2-[(tert-butyldimethylsilyl)oxy]-3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]propanoate(1.5 g, 3.13 mmol, 1.00 equiv), tetrahydrofuran (25 mL). This wasfollowed by the addition of a solution of TBAF (980 mg, 3.75 mmol, 1.20equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for 1 h at room temperature. The reactionwas then quenched by the addition of 12 mL of water/ice. The resultingsolution was extracted with 3×25 mL of ethyl acetate and the organiclayers combined. The resulting mixture was washed with 3×30 mL of brine.The mixture was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:20). This resulted in 1 g (88%) ofbenzyl(2R)3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate asyellow oil. MS (ES, m/z): 365 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.41-7.28(m, 7H), 7.11 (d, J=4.0 Hz, 2H), 6.08-6.06 (m, 1H), 5.20 (s, 2H),4.53-4.49 (m, 1H), 3.20-3.09 (m, 1H), 3.02-2.98 (m, 1H), 2.45-2.40 (m,2H), 2.02-2.00 (m, 2H), 1.60-1.52 (m, 2H), 0.99 (s, 6H).

Preparation Example 17: Preparation of Monomer M28

Monomer M28 was prepared by the process shown in Scheme 17 below.

Experimental Details

(2 S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoicacid

Into a 250-mL round-bottom flask, was placed tetrahydrofuran (140 mL),(2S)-2-amino-3-(4-tert-butylphenyl)propanoic acid (7 g, 31.63 mmol, 1.00equiv). This was followed by the addition of a solution of potassiumcarbonate (10.9 g, 78.87 mmol, 2.50 equiv) in H₂O (25 mL) dropwise withstirring at 0° C. To this was added a solution of Boc₂O (10.2 g, 46.74mmol, 1.50 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0°C. The resulting solution was stirred for 3 h at room temperature. ThepH value of the solution was adjusted to 6 with hydrogen chloride (3mol/L). The resulting solution was extracted with 3×100 mL of ethylacetate and the organic layers combined. The organic layers were washedwith 3×50 mL of brine. The layers were dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 14 g of(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoicacid as a white solid. MS (ES, m/z): 322 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoate

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (80mL),(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoicacid (10.1 g, 31.42 mmol, 1.00 equiv), Ag₂O (14.6 g, 2.00 equiv), CH₃I(5.4 g, 38.04 mmol, 1.10 equiv). The resulting solution was stirred for2 h at 60° C. in an oil bath. The reaction mixture was cooled. Theresulting solution was diluted with 200 mL of ice-water. The resultingsolution was extracted with 3×100 mL of ethyl acetate and the organiclayers combined. The organic layers were washed with 3×50 mL of brine.The organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 11.7 g (crude) of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoateas light yellow oil. MS (ES, m/z): 336 (M+H).

Methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoate

Into a 250-mL 3-necked round-bottom flask, was placedN,N-dimethylformamide (150 mL), methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-tert-butylphenyl)propanoate(11.7 g, 34.88 mmol, 1.00 equiv), Ag₂O (16 g, 3.00 equiv), CH₃I (14.7 g,103.56 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at60° C. The reaction mixture was cooled. The resulting solution wasdiluted with 400 mL of ice-water. The resulting solution was extractedwith 3×300 mL of ethyl acetate and the organic layers combined. Theorganic layers were washed with 3×100 mL of brine. The organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in 13.7 g (crude) of methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoateas light yellow oil.

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoicacid (M28)

Into a 500-mL round-bottom flask, was placed methanol (200 mL), methyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoate(13.7 g, 39.20 mmol, 1.00 equiv). This was followed by the addition of asolution of LiOH (9.4 g, 392.48 mmol, 10.00 equiv) in H₂O (40 mL)dropwise with stirring at 0° C. The resulting solution was stirred for 1h at room temperature. The resulting mixture was concentrated undervacuum. The pH value of the solution was adjusted to 7 with hydrogenchloride (12 mol/L). The resulting solution was extracted with 3×100 mLof dichloromethane and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in10 g (76%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoicacid as colorless oil. MS (ES, m/z): 336 (Ms+H); ¹HNMR (300 MHz, CDCl₃):δ 7.33-7.27 (m, 2H), 7.17-7.11 (m, 2H), 4.90-4.63 (m, 1H), 3.35-3.23 (m,1H), 3.15-2.89 (m, 1H), 2.75 (d, J=22.8 Hz, 3H), 1.47-1.23 (m, 18H).

Preparation Example 18: Preparation of Monomer M29

Monomer M29 was prepared by the process shown in Scheme 18 below.

Experimental Details

Benzyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-phenylphenyl)propanoate

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (20mL), (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-phenylphenyl)propanoicacid (3 g, 8.79 mmol, 1.00 equiv), Cs₂CO₃ (9 g, 27.62 mmol, 3.14 equiv),BnBr (1.6 g, 9.36 mmol, 1.06 equiv). The resulting solution was stirredfor 3 h at room temperature. The solids were filtered out. The resultingsolution was extracted with 3×30 mL of ethyl acetate and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:4). Thisresulted in 4.5 g of benzyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-phenylphenyl)propanoate as awhite solid. MS (ES, m/z): 432 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.59-7.11 (m, 14H), 5.23-5.19 (m, 2H), 5.05-5.04 (m, 0.5H), 4.72-4.65(m, 0.5H), 3.15-3.14 (m, 2H), 1.44 (s, 9H).

Benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoate

Benzyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-(4-phenylphenyl)propanoate (4.5g, 10.43 mmol, 1.00 equiv), Ag₂O (4.8 g), CH₃I (7.4 g, 52.13 mmol, 5.00equiv). The resulting solution was stirred for 3 h at 60° C. The solidswere filtered out. The resulting solution was extracted with 3×30 mL ofethyl acetate and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 2.4 g (52%) of benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoateas colorless oil. MS (ES, m/z): 446 (M+H); ¹HNMR (300 MHz, CD₃OD):δ7.59-7.28 (m, 14H), 5.22 (s, 2H), 4.80-4.71 (m, 1H), 3.37-3.11 (m, 2H),2.71 (s, 3H), 1.48-1.45 (m, 9H)

(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoicacid (M29)

Into a 100-mL round-bottom flask, was placed ethyl acetate (10 mL),benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoate(2.4 g, 5.39 mmol, 1.00 equiv), Palladium on carbon (0.4 g), hydrogen(enough g). The resulting solution was stirred for 1 h at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. This resulted in 1.4 g (73%) of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoicacid as colorless oil.

Preparation Example 19: Preparation of Monomer M30

Monomer M30 was prepared by the process shown in Scheme 19 below.

Experimental Details

(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid

Into a 5-L 4-necked round-bottom flask, was placed sulfuric acid/H₂O(0.5 mol/L)(3.2 L), (2R)2-amino-3-(4-bromophenyl)propanoic acid (100 g,409.69 mmol, 1.00 equiv). This was followed by the addition of asolution of NaNO₂ (350 g, 5.07 mol, 12.38 equiv) in H₂O (500 mL)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were collected by filtration.The solid was dried in an oven under reduced pressure. This resulted in146 g (73%) of (2R)3-(4-bromophenyl)-2-hydroxypropanoic acid as a whitesolid. MS (ES, m/z): 243 (M−H).

(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid

Into a 1-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dioxane (500 mL), H₂O (50 mL),(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (30 g, 122.41 mmol, 1.00equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(40 g, 190.41 mmol, 1.60 equiv), K₃PO₄ (65 g, 306.21 mmol, 2.50 equiv),Pd(dppf)Cl₂ (4.5 g, 6.15 mmol, 0.05 equiv). The resulting solution wasstirred for 2 h at 75° C. in an oil bath. The reaction mixture wascooled. The resulting mixture was concentrated under vacuum. The residuewas dissolved in 100 mL of ether. The solids were filtered out. Thesolids were dissolved in 10 mL of H₂O and 500 mL of THF. The pH value ofthe solution was adjusted to 4-5 with hydrogen chloride (12 mol/L). Thesolids were filtered out. The filtrate was dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 28 g (92%) of(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid asa light brown solid. MS (ES, m/z): 249 (M+H).

Benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate(M30)

Into a 500-mL round-bottom flask, was placed toluene (300 mL),(2R)3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoic acid (9g, 36.25 mmol, 1.00 equiv), phenylmethanol (10.3 g, 95.25 mmol, 2.50equiv), TsOH (2 g, 11.61 mmol, 0.30 equiv), 4A-MS (5.4 g). The resultingsolution was stirred for 40 min at 110° C. in an oil bath. The reactionmixture was cooled. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:3). This resulted in24 g (98%) of benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate as awhite solid. MS (ES, m/z): 339 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.62-7.30 (m, 7H), 7.13 (d, J=8.4 Hz, 2H), 6.12-6.10 (m, 1H), 5.24 (s,2H), 4.52-4.48 (m, 1H), 4.35-4.32 (m, 2H), 3.96-3.92 (m, 2H), 3.16-2.95(m, 2H), 2.67-2.49 (m, 2H).

Preparation Example 20: Preparation of Monomer M33

Monomer M33 was prepared by the process shown in Scheme 20 below.

Experimental Details

tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoate

Into a 1000-mL 3-necked round-bottom flask, was placed tert-butyl2-[(diphenylmethylidene)amino]acetate (30 g, 101.57 mmol, 1.00 equiv),toluene (315 mL), a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene(54 g, 201.55 mmol, 1.98 equiv) in chloroform (135 mL),O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (1.1 g, 2.09 mmol,0.02 equiv), potassium hydroxide (56 g, 998.04 mmol, 9.83 equiv). Theresulting solution was stirred for 3 days at −20° C. The resultingsolution was diluted with 1000 mL of EA. The resulting mixture waswashed with 3×1000 mL of H₂O. The organic layer was dried over sodiumsulfate. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was applied onto a C18 reversed phase columnwith H₂O/ACN (1/9). This resulted in 28 g (57%) of tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoateas light yellow oil. MS (ES, m/z): 482 (M+H).

tert-butyl (2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate

Into a 2-L 3-necked round-bottom flask, was placed tert-butyl(2S)-3-(4-bromo-3-fluorophenyl)-2-[(diphenylmethylidene)amino]propanoate(28 g, 58.04 mmol, 1.00 equiv), tetrahydrofuran (580 mL), citric acid(580 mL). The resulting solution was stirred for 4 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 1000 mL of water. The resultingsolution was extracted with 3×200 mL of ether and the aqueous layerscombined. The pH value of the aqueous layer was adjusted to 8 withsodium bicarbonate and extracted with 3×300 mL of ethyl acetate. Theorganic layers combined and dried over sodium sulfate and concentratedunder vacuum. This resulted in 14.8 g (80%) of tert-butyl(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate as light yellow oil.MS (ES, m/z): 318 (M+H).

(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid

Into a 500-mL round-bottom flask, was placed tert-butyl(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoate (5.9 g, 18.54 mmol,1.00 equiv), dichloromethane (200 mL), trifluoroacetic acid (21 g,185.77 mmol, 10.02 equiv). The resulting solution was stirred for 3 daysat room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a C18 reversed phase column withH₂O/ACN (1/3). This resulted in 5.4 g (crude) of(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid as a white solid.MS (ES, m/z): 262 (M+H).

(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid

Into a 500-mL 3-necked round-bottom flask, was placed(2S)-2-amino-3-(4-bromo-3-fluorophenyl)propanoic acid (5.4 g, 20.60mmol, 1.00 equiv), trifluoroacetic acid (28.3 g, 250.35 mmol, 12.15equiv), water (180 mL), to the above was added a solution of NaNO₂ (17.1g, 247.83 mmol, 12.03 equiv) in water (180 mL) slowly. The resultingsolution was stirred for 16 h at room temperature. The solids werecollected by filtration. This resulted in 3.1 g (57%) of(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid as a lightyellow solid.

(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid (3 g, 11.40mmol, 1.00 equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.8 g, 22.85 mmol, 2.00 equiv), K₃PO₄ (7.28 g, 34.30 mmol, 3.01 equiv),dioxane (180 mL), water (18 mL), Pd(dppf)Cl₂ (1.67 g, 2.28 mmol, 0.20equiv). The resulting solution was stirred for 5 h at 80° C. Theresulting mixture was concentrated under vacuum. The resulting mixturewas diluted with 900 mL of ether. The solids were collected byfiltration. The solids were dissolved in 200 mL of tetrahydrofuran. ThepH value of the solution was adjusted to 3-4 with hydrogen chloride. Thesolid was filtered out. The filtrate was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/10). This resulted in 2.63 g (87%) of(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid as brown solid. MS (ES, m/z): 265 (M−H).

Benzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoate(M33)

Into a 100-mL round-bottom flask, was placed(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoicacid (1 g, 3.76 mmol, 1.00 equiv), BnOH (1.1 g), TsOH (160 mg, 0.93mmol, 0.25 equiv), 4A-Ms (1 g), toluene (20 mL). The resulting solutionwas stirred for 4 h at 110° C. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/4). This resulted in 350 mg (26%) ofbenzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoateas brown oil. ¹HNMR (300 MHz, CD₃OD): δ 7.37-7.29 (m, 5H), 7.20-7.15 (m,1H), 6.97-6.92 (m, 2H), 6.02 (br, 1H), 5.19 (s, 2H), 4.44-4.40 (m, 1H),4.30-4.27 (m, 2H), 3.92-3.885 (m, 2H), 3.33-2.90 (m, 2H), 2.47-2.46 (m,2H).

Preparation Example 21: Preparation of Monomer M34

Monomer M34 was prepared by the process shown in Scheme 21 below.

Experimental Details

(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoic acid

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dioxane/H₂O (20/2 mL),(2S)-3-(4-bromo-3-fluorophenyl)-2-hydroxypropanoic acid (830 mg, 3.16mmol, 1.00 equiv),2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (790 mg,3.80 mmol, 1.20 equiv), Pd(dppf)Cl₂ (115 mg, 0.16 mmol, 0.05 equiv),K₃PO₄ (2 g, 9.42 mmol, 3.00 equiv). The resulting solution was stirredfor 1 h at 80° C. in an oil bath. The reaction mixture was cooled. Theresulting mixture was concentrated under vacuum. The residue wasdissolved in 20 mL of ether. The solids were filtered out. The filtratewas concentrated under vacuum. The residue was dissolved in 20 mL ofTHF. The pH value of the solution was adjusted to 4 with hydrogenchloride (12 mol/L). The solids were filtered out. The filtrate wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 1 g of(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoic acidas a brown solid. MS (ES, m/z): 263 (M−H).

Benzyl(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoate (M34)

Into a 100-mL round-bottom flask, was placed tol (40 mL),(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoic acid(1 g, 3.78 mmol, 1.00 equiv), BnOH (0.8 g, 2.00 equiv), TsOH (130 mg,0.75 mmol, 0.20 equiv), 4A-Ms (0.3 g). The resulting solution wasstirred for 2 h at 110° C. in an oil bath. The reaction mixture wascooled. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:20-1:10). This resulted in 730 g (crude) of benzyl(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoate ascolorless oil. MS (ES, m/z): 355 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.41-7.33 (m, 5H), 7.14-7.08 (m, 1H), 6.88-6.83 (m, 2H), 5.92 (m, 1H),5.25 (s, 2H), 4.45-4.47 (m, 1H), 3.13-2.91 (m, 2H), 2.35 (br, 2H), 2.22(br, 2H), 1.87-1.58 (m, 4H).

Preparation Example 22: Preparation of Monomer M35

Monomer M35 was prepared by the process shown in Scheme 22 below.

Experimental Details

Benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]propanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2R)-3-(4-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (5 g,11.12 mmol, 1.00 equiv), toluene (100 mL), 3,3-difluoropyrrolidinehydrochloride (4.7 g, 32.74 mmol, 3.00 equiv), X-Phos (2.1 g, 0.40equiv), Pd(OAc)₂ (500 mg, 2.23 mmol, 0.20 equiv), Cs₂CO₃ (14.3 g, 43.89mmol, 4.00 equiv). The resulting solution was stirred overnight at 90°C. The solids were filtered out. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:30). This resulted in 4.2 g (79%) ofbenzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]propanoateas yellow oil. MS (ES, m/z): 476 (M+H); 1H NMR (CDCl₃, 300 MHz) δ:7.37-7.30 (m, 5H), 7.10 (d, J=4.4 Hz, 2H), 6.50 (d, J=4.2 Hz, 2H),5.20-5.10 (m, 2H), 4.38-4.33 (m, 1H), 3.66 (t, J=13.2 Hz, 2H), 3.51 (t,J=6.9 Hz, 2H), 3.04-2.98 (m, 1H), 2.90-2.83 (m, 1H), 2.58-2.46 (m, 2H),0.79 (s, 9H), −0.10 (s, 3H), −0.15 (s, 3H).

Benzyl(2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate (M35)

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]propanoate(4.2 g, 8.83 mmol, 1.00 equiv), tetrahydrofuran (80 mL). This wasfollowed by the addition of TBAF (4.6 g, 17.59 mmol, 2.00 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for30 min at room temperature. The reaction was then quenched by theaddition of 100 mL of water/ice. The resulting solution was extractedwith 3×100 mL of ethyl acetate and the organic layers combined.

The organic phase was washed with 3×50 mL of brine. The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:15). This resulted in 2.5 g (78%) of benzyl(2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate asyellow oil. MS (ES, m/z): 362 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 7.38-7.24(m, 5H), 7.04 (d, J=4.0 Hz, 2H), 6.51 (d, J=4.4 Hz, 2H), 5.54-5.52 (m,1H), 5.08 (s, 2H), 4.25-4.19 (m, 1H), 3.64 (t, J=13.5 Hz, 2H), 3.42 (t,J=6.9 Hz, 2H), 2.90-2.74 (m, 2H), 2.58-2.44 (m, 2H).

Preparation Example 23: Preparation of Monomer M45

Monomer M45 was prepared by the process shown in Scheme 23 below.

Experimental Details

Methyl(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed Zn (1.35 g),N,N-dimethylformamide (100 mL). This was followed by the addition of I₂(188.1 mg) in several batches at 50° C. in 10 min. To this was addedmethyl (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-iodopropanoate (6 g,18.23 mmol, 1.00 equiv) in several batches at 0° C. in 30 min. To themixture was added 2-bromo-5-(trifluoromethyl)pyridine (3.3 g, 14.60mmol, 0.80 equiv) in several batches at 0° C. To the mixture was addedPd(PPh₃)₂Cl₂ (1.04 g, 1.48 mmol, 0.08 equiv) in several batches at 0° C.The resulting solution was stirred for 5 h at 50° C. The reactionmixture was cooled. The solids were filtered out. The resulting solutionwas diluted with 50 mL of H₂O. The resulting solution was extracted with3×100 mL of ethyl acetate and the organic layers combined. The organicphase was washed with 6×100 mL of brine. The organic phase was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:4). The collected fractions were combined and concentrated undervacuum. This resulted in 5 g (79%) of methyl(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoateas yellow oil. MS (ES, m/z): 349 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.80(s, 1H), 7.89-7.86 (m, 1H), 7.32 (d, J=4.5 Hz, 1H), 5.80-5.60 (m, 1H),4.77-4.75 (m, 1H), 3.73 (s, 3H), 3.42-3.41 (m, 2H), 1.43 (s, 9H).

(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoicacid

Into a 250-mL round-bottom flask, was placed methyl(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate(5 g, 14.35 mmol, 1.00 equiv), methanol (60 mL), to the above was addeda solution of sodium hydroxide (1.7 g, 42.50 mmol, 2.96 equiv) in water(15 mL). The resulting solution was stirred for 12 h at 25° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with 10 mL of H₂O. The pH value of the solution was adjustedto 6 with sulfuric acid (1 mol/L). The resulting solution was extractedwith 3×50 mL of ethyl acetate and the organic layers combined. Theorganic phase was washed with 3×100 mL of brine. The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 4.2 g (88%) of(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoicacid as yellow oil. MS (ES, m/z): 335 (M+H).

(2R)-2-amino-3-[5-(trifluoromethyl)pyridin-2-yl]propanoic acid

Into a 100-mL round-bottom flask, was placed(2R)-2-[[(tert-butoxy)carbonyl]amino]-3-[5-(trifluoromethyl)pyridin-2-yl]propanoicacid (3 g, 8.97 mmol, 1.00 equiv), dichloromethane (30 mL),trifluoroacetic acid (6 mL). The resulting solution was stirred for 2 hat 25° C. The resulting mixture was concentrated under vacuum. Thisresulted in 4 g (crude) of(2R)-2-amino-3-[5-(trifluoromethyl)pyridin-2-yl]propanoic acid;trifluoroacetic acid as brown oil. MS: (ES, m/z): 235 (M+H); ¹H NMR(DMSO, 300 MHz) δ: 8.89 (s, 1H), 8.22-8.21 (br s 3H), 8.19-8.18 (m, 1H),7.65-7.54 (m, 1H), 4.46 (br s, 1H), 3.50-3.35 (m, 2H).

(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoic acid

Into a 250-mL round-bottom flask, was placed water (76 mL). This wasfollowed by the addition of sulfuric acid (7.5 g, 76.47 mmol, 6.34equiv) dropwise with stirring at 0° C. To this was added(2R)-2-amino-3-[5-(trifluoromethyl)pyridin-2-yl]propanoic acid;trifluoroacetic acid (4.2 g, 12.06 mmol, 1.00 equiv), NaNO₂ (1.75 g,25.36 mmol, 2.10 equiv). The resulting solution was stirred for 12 h at25° C. The resulting solution was extracted with 5×100 mL of ethylacetate and the organic layers combined. The organic phase was washedwith 3×100 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 2.5 g(88%) of (2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoicacid as yellow oil. MS (ES, m/z): 236 M+H).

Benzyl-(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate(M45)

Into a 250-mL round-bottom flask, was placed(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoic acid (2 g,8.50 mmol, 1.00 equiv), N,N-dimethylformamide (100 mL), Cs₂CO₃ (13.87 g,42.57 mmol, 5.01 equiv). This was followed by the addition of(bromomethyl)benzene (2.89 g, 16.90 mmol, 1.99 equiv) dropwise at 0° C.in 10 min. The resulting solution was stirred for 12 h at 25° C. Thesolids were filtered out. The resulting solution was diluted with 100 mLof H₂O. The resulting solution was extracted with 3×100 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 6×100 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:4). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 1.9 g (69%) of benzyl(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate as lightyellow oil. MS (ES, m/z): 326 (M+H); ¹H NMR (DMSO, 300 MHz) δ: 8.85 (d,J=5.3 Hz, 1H), 8.10-8.07 (m, 1H), 7.54-7.50 (m, 1H), 7.38-7.29 (m, 5H),5.74-5.65 (m, 1H), 5.12 (s, 2H), 4.61-4.54 (m, 1H), 3.25-3.11 (m, 2H).

Preparation Example 24: Preparation of Monomer M46

Monomer M46 was prepared by the process shown in Scheme 24 below.

Experimental Details

Methyl 4-(5-bromopyridin-2-yl)oxane-4-carboxylate

Into a 1000-mL 3-necked round-bottom flask, was placed tetrahydrofuran(300 mL), 5-bromo-2-fluoropyridine (13 g, 73.87 mmol, 1.00 equiv),methyl oxane-4-carboxylate (17 g, 117.92 mmol, 1.60 equiv). This wasfollowed by the addition of KHMDS (300 mL) dropwise with stirring at−30° C. The resulting solution was stirred for 3 h at room temperature.The reaction was then quenched by the addition of 100 mL of NH₄Cl. Theresulting solution was extracted with 3×120 mL of ethyl acetate and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 22 g (99%) of methyl4-(5-bromopyridin-2-yl)oxane-4-carboxylate as a solid. MS (ES, m/z): 301(M+H).

4-(5-bromopyridin-2-yl)oxane-4-carboxylic acid

Into a 50-mL round-bottom flask, was placed methanol (5 mL), water (1mL), methyl 4-(5-bromopyridin-2-yl)oxane-4-carboxylate (500 mg, 1.67mmol, 1.00 equiv), LiOH (80 mg, 3.34 mmol, 2.01 equiv). The resultingsolution was stirred for 3 h at room temperature. The resulting mixturewas concentrated under vacuum.

This resulted in 420 mg (88%) of4-(5-bromopyridin-2-yl)oxane-4-carboxylic acid as a yellow solid. MS(ES, m/z): 287 (M+H).

5-Bromo-2-(oxan-4-yl)pyridine

Into a 1000-mL round-bottom flask, was placed DMSO (200 mL),4-(5-bromopyridin-2-yl)oxane-4-carboxylic acid (20 g, 69.90 mmol, 1.00equiv), water (60 mL), sodium chloride (16 g). The resulting solutionwas stirred for 3 h at 150° C. The resulting solution was diluted with500 mL of water/ice. The resulting solution was extracted with 3×300 mLof ethyl acetate and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in10 g (59%) of 5-bromo-2-(oxan-4-yl)pyridine as a yellow solid. MS (ES,m/z): 243 (M+H).

Methyl-(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoate

Into a 250-mL 3-necked round-bottom flask, was placedN,N-dimethylformamide (40 mL), Zn (26 g), I₂ (4 g), methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-iodopropanoate (10 g, 30.38mmol, 1.00 equiv), Pd(PPh₃)₂Cl₂ (1.6 g, 2.28 mmol, 0.08 equiv),5-bromo-2-(oxan-4-yl)pyridine (17 g, 70.22 mmol, 2.31 equiv). Theresulting solution was stirred overnight at 50° C. The solids werefiltered out. The resulting solution was extracted with 3×50 mL of ethylacetate and the organic layers combined and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (3:1). Thisresulted in 4 g (36%) of methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoateas yellow oil. MS (ES, m/z): 365 (M+H).

(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoicacid

Into a 50-mL round-bottom flask, was placed water (2 mL), methanol (10mL), LiOH (420 mg, 17.54 mmol, 3.20 equiv), methyl(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoate(2 g, 5.49 mmol, 1.00 equiv). The resulting solution was stirred for 3 hat room temperature. The resulting mixture was concentrated undervacuum. This resulted in 1.5 g (78%) of(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoicacid as a yellow crude solid. MS (ES, m/z): 351 (M+H).

(2S)-2-amino-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid

Into a 50-mL round-bottom flask, was placed dichloromethane (10 mL),(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-[6-(oxan-4-yl)pyridin-3-yl]propanoicacid (900 mg, 2.57 mmol, 1.00 equiv), trifluoroacetic acid (3 mL). Theresulting solution was stirred for 3 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 700 mg(crude) of (2S)-2-amino-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid. MS(ES, m/z): 251 (M+H).

(2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid

Into a 100-mL round-bottom flask, was placed water (20 mg),trifluoroacetic acid (1.6 g, 14.15 mmol, 5.90 equiv),(2S)-2-amino-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid (600 mg, 2.40mmol, 1.00 equiv). This was followed by the addition of a solution ofNaNO₂ (1 g, 14.49 mmol, 6.05 equiv) in water (10 mL) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was diluted in DCM:MeOH (15:1, 50 mL). The solid was filteredout. The filtrate was concentrated under vacuum. This resulted in 300 mg(50%) of (2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid asyellow crude oil. MS (ES, m/z): 252 (M+H).

Benzyl-(2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoate (M46)

Into a 100-mL round-bottom flask, was placed N,N-dimethylformamide (15mL), (2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoic acid (2 g,7.96 mmol, 1.00 equiv), Cs₂CO₃ (5 g, 15.35 mmol, 1.93 equiv), BnBr (2.6g, 15.20 mmol, 1.91 equiv). The resulting solution was stirred for 2 hat room temperature. The solids were filtered out. The resultingsolution was extracted with 3×30 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 2.7 g (99%) of benzyl(2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoate as yellow oil. MS(ES, m/z): 342 (M+H); ¹HNMR (300 MHz, CDCl₃): δ 8.37 (d, J=2.1 Hz, 1H),7.48-7.45 (m, 1H), 7.41-7.33 (m, 5H), 7.06 (d, J=8.1 Hz, 1H), 5.21 (s,2H), 4.50-4.46 (m, 1H), 4.12-4.07 (m, 2H), 3.59-3.51 (m, 2H), 3.14-2.89(m, 3H), 1.89-1.82 (m, 4H).

Preparation Example 25: Preparation of Monomer M47

Monomer M47 was prepared by the process shown in Scheme 25 below.

Experimental Details

(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dioxane/H₂O (88 mL),(2R)-3-(4-bromophenyl)-2-hydroxypropanoic acid (4 g, 16.32 mmol, 1.00equiv),2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.0 g, 16.39 mmol, 1.00 equiv), Pd(dppf)Cl₂ (640 mg, 0.87 mmol, 0.05equiv), K₃PO₄ (11 g, 51.82 mmol, 3.00 equiv). The resulting solution wasstirred for 4 h at 80° C. in an oil bath. The reaction mixture wascooled. The resulting mixture was concentrated under vacuum. The residuewas dissolved in 50 mL of ether. The solids were collected byfiltration. The solids were dissolved in 50 mL of THF. The pH value ofthe solution was adjusted to 5 with hydrogen chloride (12 mol/L). Theresulting solution was diluted with 200 mL of ethyl acetate. The solidswere collected by filtration. The filtrate was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 4.5 g(98%) of(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid as light yellow oil. MS (ES, m/z): 281 (M−H).

Benzyl-(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate(M47)

Into a 500-mL round-bottom flask, was placed toluene (200 mL),(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoicacid (4.5 g, 15.94 mmol, 1.00 equiv), BnOH (2.24 g, 1.30 equiv), TsOH(540 mg, 3.14 mmol, 0.20 equiv), 4A-MS (2 g). The resulting solution wasstirred for 4 h at 110° C. in an oil bath. The reaction mixture wascooled. The solids were filtered out. The filtrate mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:20-1:10). This resulted in5 g (84%) of benzyl(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate asa light yellow solid. ¹HNMR (300 MHz, CDCl₃): δ 7.62-7.30 (m, 7H), 7.11(d, J=8.4 Hz, 2H), 5.89 (br, 1H), 5.21 (s, 2H), 4.52-4.48 (m, 1H),3.16-2.95 (m, 2H), 2.71-2.67 (m, 4H), 2.25-2.12 (m, 2H).

Preparation Example 26: Preparation of Monomer M48

Monomer M48 was prepared by the process shown in Scheme 26 below.

Experimental Details

4-(4-Bromonaphthalen-1-yl)morpholine

Into a 250-mL round-bottom flask, was placed 4-bromonaphthalen-1-amine(5 g, 22.51 mmol, 1.00 equiv), 1-bromo-2-(2-bromoethoxy)ethane (8 g,34.50 mmol, 1.53 equiv), N,N-dimethylformamide (100 mL), potassiumcarbonate (14 g, 101.30 mmol, 4.50 equiv). The resulting solution wasstirred overnight at 110° C. The solids were filtered out. The resultingsolution was quenched with 200 mL of water, extracted with 2×50 mL ofethyl acetate and the organic layers combined. The organic phase waswashed with 2×20 mL of water. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 3.5 g (53%) of 4-(4-bromonaphthalen-1-yl)morpholine as brownoil. MS (ES, m/z): 292 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.29-8.25 (m,2H), 7.73 (d, J=4.0 Hz, 1H), 7.64-7.59 (m, 2H), 6.98 (d, J=4.0 Hz, 1H),4.00 (t, J=4.5 Hz, 4H), 3.11 (t, J=4.5 Hz, 4H).

Benzyl (2E)-3-[4-(morpholin-4-yl)naphthalen-1-yl]prop-2-enoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 4-(4-bromonaphthalen-1-yl)morpholine(3 g, 10.27 mmol, 1.00 equiv), benzyl prop-2-enoate (2.0 g, 12.33 mmol,1.20 equiv), N,N-dimethylformamide (100 mL), Bu₄NCl (5.7 g, 20.51 mmol,2.00 equiv), sodium bicarbonate (4.3 g, 51.18 mmol, 4.98 equiv),Pd(OAc)₂ (230 mg, 1.02 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 110° C. The solids were filtered out. The resultingsolution was quenched with 200 mL of water, extracted with 2×50 mL ofethyl acetate and the organic layers combined. The organic phase waswashed with 2×30 mL of water and 1×30 mL of brine. The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 2.3 g (60%) of benzyl(2E)-3-[4-(morpholin-4-yl)naphthalen-1-yl]prop-2-enoate as yellow oil.MS (ES, m/z): 374 (M+H).

Benzyl (2R,3S)-2,3-dihydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate

Into a 250-mL round-bottom flask, was placed benzyl(2E)-3-[4-(morpholin-4-yl)naphthalen-1-yl]prop-2-enoate (2.1 g, 5.62mmol, 1.00 equiv), tert-butanol (40 mL), water (40 mL),methane-sulfonamide (600 mg, 6.31 mmol, 1.12 equiv), AD-mix-α (8 g). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 11.5 g of Na₂SO₃. Thesolids were filtered out. The resulting solution was diluted with 200 mLof water, extracted with 2×50 mL of ethyl acetate and the organic layerscombined. The organic phase was washed with 2×30 mL of water and 1×30 mLof brine. The organic phase was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:4). This resulted in 1.6 g(70%) of benzyl (2R,3S)-2,3-dihydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate asbrown oil. MS (ES, m/z): 408 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.34-8.31(m, 1H), 8.06-8.03 (m, 1H), 7.66 (d, J=3.9 Hz, 1H), 7.58-7.52 (m, 2H),7.41-7.31 (m, 5H), 7.13 (d, J=4.0 Hz, 1H), 5.84 (br s 1H), 5.34-5.21 (m,2H), 4.73 (br s, 1H), 4.63-4.60 (m, 1H), 4.00 (t, J=4.5 Hz, 4H),3.80-3.66 (m, 1H), 3.16-3.11 (m, 4H).

Benzyl (2R)-2-hydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate

Into a 250-mL round-bottom flask, was placed benzyl (2R,3S)-2,3-dihydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate (1.6g, 3.93 mmol, 1.00 equiv), dichloromethane (100 mL), Et₃SiH (1.35 g,11.61 mmol, 2.96 equiv), trifluoroacetic acid (1.3 g, 11.50 mmol, 2.93equiv). The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of 40 mL ofwater. The resulting solution was extracted with 2×50 mL ofdichloromethane and the organic layers combined. The organic phase waswashed with 3×30 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 600 mg (39%) of benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate as yellowoil. MS (ES, m/z): 392 (M+H); ¹H NMR (CDCl₃, 300 MHz) δ: 8.38-8.36 (m,1H), 8.11-8.08 (m, 1H), 7.58-7.52 (m, 2H), 7.40-7.28 (m, 6H), 7.08 (d,J=3.8 Hz, 1H), 5.24-5.14 (m, 2H), 4.66-4.62 (m, 1H), 4.07 (t, J=4.5 Hz,4H), 3.69-3.63 (m, 1H), 3.37-3.29 (m, 1H), 3.19-3.10 (m, 4H).

Preparation Example 27: Preparation of Monomer M49

Monomer M49 was prepared by the process shown in Scheme 27 below.

Experimental Details

methyl(2R)-2-(tert-butoxycarbonylamino)-3-[6-(trifluoromethyl)-3-pyridyl]propanoate

To a stirred mixture of zinc powder (0.7 g, 11 mmol) and iodine (0.1 g,0.4 mmol) in 5 mL DMF under nitrogen atmosphere and cooled to 0° C. wasadded dropwise a solution of (S)—N-tert-butoxycarbonyl-beta-iodoalaninemethyl ester (2.5 g, 7.6 mmol) in 10 mL DMF and the mixture stirred 30min. The mixture was then treated with 5-bromo-2-trifluoromethylpyridine(1.7 g, 7.6 mmol) and bis-triphenylphosphine-palladium(II)chloride (0.26g, 0.4 mmol) and heated 5 h at 50° C. The mixture was then cooled toroom temperature, filtered through a celite plug, the filtrate dilutedwith 200 mL water and extracted into 200 mL ethyl acetate. The organiclayer was washed with 100 mL 20% LICl solution, washed with brine, driedover sodium sulfate, filtered, concentrated and the residue purified onsilica gel column eluting with ethyl acetate/heptanes to obtain thetarget compound as a yellow oil. Yield: 1.4 g, 54%. MS (CI, m/z): 349(M+H); ¹H NMR (CDCl₃): δ 8.51 (s, 1H), 7.66 (m, 2H), 5.10 (m, 1H), 4.65(m, 1H), 3.77 (s, 3H), 3.29 (m, 1H), 3.11 (m, 1H), 1.41 (s, 9H); ¹⁹F NMR(CDCl₃): δ 67.35 (s, 3F).

(2R)-2-(tert-butoxycarbonylamino)-3-[6-(trifluoromethyl)-3-pyridyl]propanoicacid

To a stirred solution of methyl(2R)-2-(tert-butoxycarbonylamino)-3-[6-(trifluoromethyl)-3-pyridyl]propanoate(1.4 g, 4.0 mmol) in 15 mL 2:1 methanol:THF was added a solution ofsodium hydroxide (0.32 g, 8.1 mmol) in 7 mL water and the mixturestirred 1 h. The mixture was diluted with 60 mL water, acidified to pH 2with 1 M HCl and extracted into 75 mL ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, filtered andconcentrated to obtain the target compound as a clear oil. Yield: 1.4 g(quantitative). MS (CI, m/z): 335 (M+H).

(2R)-2-amino-3-[6-(trifluoromethyl)-3-pyridyl]propanoic acidhydrochloride salt

To 10 mL of a 4 M solution of HCl in dioxane was added(2R)-2-(tert-butoxycarbonylamino)-3-[6-(trifluoromethyl)-3-pyridyl]propanoicacid (1.4 g, 4.0 mmol) and the mixture stirred 1 h. The mixture wasconcentrate and the residue dried under high vacuum to obtain the targetcompound as a clear oil. Yield: 1.1 g (quantitative). Mass spec (CI)m/z: (M+H)+235.

(2R)-2-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]propanoic acid

To a stirred mixture of(2R)-2-amino-3-[6-(trifluoromethyl)-3-pyridyl]propanoic acidhydrochloride salt (1.1 g, 4.0 mmol) in 16 mL 0.5 M sulfuric acidsolution (8.0 mmoL) cooled to 0° C. was added dropwise a solution ofsodium nitrite (1.7 g, 24 mmol) in 6 mL water and the mixture stirred 1h. The mixture was diluted with 50 mL water and extracted into 75 mLethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated to obtain the target compoundas a yellow solid. Yield (0.90 g, 94%). MS (CI, m/z): 236 (M+H); ¹H NMR(CDCl₃): δ 8.67 (m, 1H), 7.92 (m, 1H), 7.71 (m, 1H), 4.61 (m, 1H), 3.45(m, 1H), 3.25 (m, 1H); ¹⁹F NMR (CDCl₃): δ 67.35 (s, 3F).

benzyl (2R)-2-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]propanoate (M49)

To a stirred solution of(2R)-2-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]propanoic acid (0.90 g,3.8 mmol) in 10 mL DMF was added cesium carbonate (1.2 g, 3.8 mmol) andthe mixture stirred 30 min. The mixture was then treated with benzylbromide (0.65 g, 3.8 mmol) and the mixture stirred overnight. Themixture was diluted with 60 mL water and extracted into 75 mL ethylacetate. The organic layer was washed with 50 mL 20% LICl solution,washed with brine, dried over sodium sulfate, filtered, concentrated andthe residue purified on silica gel column eluting with ethylacetate/heptanes to obtain the target compound as a clear oil. Yield:0.57 g, 46%. MS (CI m/z): 326 (M+H); ¹H NMR (CDCl₃): δ 8.55 (d, J=1.7Hz, 1H), 7.64 (dd, J=1.7, 8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.40 (m,3H), 7.34 (m, 2H), 5.22, (q, J=11.9 Hz, 2H), 4.52 (m, 1H), 3.21 (m, 1H),3.05 (m, 1H), 2.93 (d, J=4.8 Hz, 1H); ¹⁹F NMR (CDCl₃): δ 67.87 (s, 3F).

Preparation Example 28: Preparation of Monomer M50

Monomer M50 was prepared according to the process shown in Scheme 28below:

Experimental Details

Tert-butyl(2S)-2-[(diphenylmethylidene)amino]-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butyl2-[(diphenylmethylidene)amino]acetate (14.6 g, 49.5 mmol, 1.00 eq.) intoluene (150 mL). To this was added(2S,4S,5R)-1-(anthracen-9-ylmethyl)-5-ethenyl-2-[(R)-(prop-2-en-1-yloxy)(quinolin-4-yl)methyl]-1-azabicyclo[2.2.2]octan-1-iumbromide (3 g, 4.95 mmol, 0.10 eq.). This was followed by the addition ofa solution of 1-(bromomethyl)-4-[(trifluoromethyl)sulfanyl]benzene (20g, 74 mmol, 1.5 eq.) in chloroform (65 mL) dropwise with stirring at−20° C. in 5 min. To the mixture was added a solution of potassiumhydroxide (41.6 g, 0.75 mol, 15 eq.) in water (80 mL) dropwise withstirring at −20° C. The resulting solution was stirred overnight at −20°C. The resulting solution was diluted with 500 mL of EA. The resultingmixture was washed with 3×300 mL of H₂O and 3×200 mL of brine. Theorganic phase was collected and dried over anhydrous sodium sulfate. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 24 g (99%) oftert-butyl(2S)-2-[(diphenylmethylidene)amino]-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoateas yellow oil. MS (ES, m z): 486 (M+H).

Tert-butyl(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate

Into a 3000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of tert-butyl(2S)-2-[(diphenylmethylidene)amino]-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate(24 g, 32.8 mmol, 1.00 eq.) in tetrahydrofuran (500 mL). To the abovewas added a solution of citric acid (32 g, 5.00 eq.) in water (500 mL).The resulting solution was stirred for 2 h at room temperature. The lowboiling point solution was removed under vacuum. The resulting mixturewas washed with 2×100 mL of DCM. The aqueous solution was collected andthe pH value was adjusted to 7-8 with sodium bicarbonate/H₂O. Theaqueous was extracted with 2×500 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 15 g (94%) of tert-butyl(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate ascolorless oil. MS (ES, m/z): 322 (M+H).

(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid

Into a 1000-mL 3-necked round-bottom flask, was placed a solution oftert-butyl(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate (15 g, 47mmol, 1.00 eq.) in dichloromethane (100 mL), trifluoroacetic acid (250mL). The resulting solution was stirred overnight at room temperature.The resulting mixture was concentrated under vacuum. This resulted in17.2 g (crude) of(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid as agray solid. MS (ES, m/z): 266 (M+H).

(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid

Into a 1000-mL 3-necked round-bottom flask, was placed a solution of(2S)-2-amino-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid (17.2g, crude) in H₂O (360 mL) and TFA (62 g). To the above was added asolution of NaNO₂ (37.5 g) in water (360 mL) dropwise with stirred at 0°C. The resulting solution was stirred overnight at room temperature. Thesolids were collected by filtration. This resulted in 10.3 g (60%) of(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid asa white solid. MS (ES, m/z): 265 (M−H).

Benzyl (2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate(M50)

Into a 500-mL 3-necked round-bottom flask, was placed a solution of(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoic acid(10.3 g, 38.7 mmol, 1.00 eq.) in N,N-dimethylformamide (200 mL), Cs₂CO₃(37.8 g, 116.1 mmol, 3.00 eq.). This was followed by the addition ofBnBr (7.3 g, 42.6 mmol, 1.10 eq.) dropwise. The resulting solution wasstirred for 2 h at room temperature. The resulting solution was dilutedwith 1000 mL of EA. The resulting mixture was washed with 3×300 mL ofH₂O and 3×300 mL of Brine. The organic phase was collected and driedover anhydrous sodium sulfate. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:20-1:1). Thisresulted in 8.1 g (58.8%) of benzyl(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate as awhite solid.

Preparation Examples 29-88 below show how to prepare various dimercompounds from the certain of monomers M1 to M50 described above, whichare used to prepare the compounds of the invention.

Preparation Example 29: Preparation of Dimer D1

Dimer D1 was prepared by the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tertbutoxy)carbonyl](methyl)amino]-4-methylpentanoate (D1)

Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(200 mg, 0.82 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (152 mg, 0.47mmol, 1.00 equiv), dichloromethane (10 mL). This was followed by theaddition of DCC (140 mg, 0.68 mmol, 1.10 equiv), 4-dimethylaminopyridine(83 mg, 0.68 mmol, 1.10 equiv) and HOBT (116 mg, 0.86 mmol, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:20). Thisresulted in 159.3 mg (35%) of(2R)1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas a light yellow solid. MS (ES, m/z): 552 (M+H); ¹H NMR (300 MHz,CDCl₃): δ 7.52-7.47 (m, 2H), 7.36-7.34 (m, 3H), 7.26-7.24 (m, 4H),5.32-5.28 (m, 1H), 4.18-4.99 (m, 2H), 4.97-4.67 (m, 1H), 3.26-3.13 (m,2H), 2.62 (d, J=21.9 Hz, 3H), 1.60-1.14 (m, 12H), 0.93 (d, J=12.0 Hz,6H).

Preparation Example 30: Preparation of Dimer D2

Dimer D2 was prepared by the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D2)

Into a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (15 g, 56.97 mmol, 1.00 equiv) in dichloromethane (400 mL), benzyl(2R)2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (12 g, 37.00 mmol,1.00 equiv). This was followed by the addition of HOBT (7.5 g, 55.51mmol, 1.20 equiv), DCC (11 g, 53.31 mmol, 1.20 equiv) and4-dimethylaminopyridine (6.8 g, 55.66 mmol, 1.20 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 21 g (65%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas red oil. MS (ES, m/z): 570 (M+H).

Preparation Example 31: Preparation of Dimer D3

Dimer D3 was prepared by the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate(D3)

Into a 50-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(4 g, 15.42 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (5 g, 15.42 mmol,1.00 equiv), dichloromethane (40 mL). This was followed by the additionof DCC (4.1 g, 1.30 equiv), HOBT (2.7 g, 1.30 equiv) and4-dimethylaminopyridine (2.5 g, 1.30 equiv) respectively in portionswith stirring at 0° C. The resulting solution was stirred for 14 h atroom temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:50). This resulted in 6 g(69%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoateas a white solid. MS (ES, m/z): 566 (M+H); ¹H NMR (300 MHz, DMSO): δ7.61-7.59 (m, 2H), 7.45-7.42 (m, 2H), 7.37-7.35 (m, 3H), 7.29 (br, 2H),5.41-5.35 (m, 1H), 5.13 (s, 2H), 4.90-4.85 (m, 0.5H), 4.59 (br, 0.5H),3.32-3.15 (m, 2H), 2.55-2.50 (m, 3H), 1.51-1.46 (m, 2H), 1.37 (d, J=21.0Hz, 9H), 0.83 (s, 9H).

Preparation Example 32: Preparation of Dimer D4

Dimer D4 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D4)

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)3-(4-fluorophenyl)-2-hydroxypropanoate (1.5 g, 5.47 mmol, 1.00equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoicacid (1.5 g, 6.11 mmol, 1.10 equiv), dichloromethane (80 mL). This wasfollowed by the addition of DCC (1.2 g, 5.82 mmol, 1.10 equiv), HOBT(0.8 g, 1.10 equiv) and 4-dimethylaminopyridine (0.7 g, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred for 13 h at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 1.5 g (55%) of(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas a white solid. MS (ES, m/z): 502 (M+H); ¹H NMR (300 MHz, DMSO): δ7.41-7.21 (m, 7H), 7.09-7.03 (m, 2H), 5.31-5.29 (m, 1H), 5.13 (s, 2H),4.82-4.78 (m, 0.5H), 4.58-4.54 (m, 0.5H), 3.19-3.05 (m, 2H), 2.56 (s,3H), 1.52-1.23 (m, 12H), 0.90-0.79 (br, 6H).

Preparation Example 33: Preparation of Dimer D5

Dimer D5 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D5)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed dichloromethane (60 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (2.8 g, 10.63 mmol, 1.00 equiv), benzyl(2R)3-(4-fluorophenyl)-2-hydroxypropanoate (2.9 g, 10.57 mmol, 1.00equiv). This was followed by the addition of DCC (2.4 g, 88.75 mmol,1.10 equiv), 4-dimethylaminopyridine (1.4 g, 11.46 mmol, 1.10 equiv) andHOBT (1.58 g, 49.62 mmol, 1.10 equiv) respectively in portions at 0° C.The resulting solution was stirred overnight at room temperature. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:100-1:50). This resulted in 3.8 g (crude) of(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a yellow solid. MS (ES, m/z): 520 (M+H).

Preparation Example 34: Preparation of Dimer D6

Dimer D6 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate(D6)

Into a 100-mL round-bottom flask, was placed dichloromethane (20 mL),benzyl (2R)3-(4-fluorophenyl)-2-hydroxypropanoate (2 g, 7.29 mmol, 1.00equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(2 g, 7.71 mmol, 1.06 equiv). This was followed by the addition of DCC(4.6 g, 22.29 mmol, 3.06 equiv), 4-dimethylaminopyridine (2.2 g, 18.01mmol, 2.47 equiv) and HOBT (2.4 g, 17.76 mmol, 2.44 equiv) respectivelyin portions with stirring at 0° C. The resulting solution was stirredfor 2 h at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:5). This resulted in 2.6 g (69%) of(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoateas colorless oil. MS (ES, m/z): 416 (M+H-Boc).

Preparation Example 35: Preparation of Dimer D7

Dimer D7 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (D7)

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (10 g, 29.29 mmol,1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(7.9 g, 32.20 mmol, 1.10 equiv), dichloromethane (180 mL). This wasfollowed by the addition of DCC (6.6 g, 31.99 mmol, 1.10 equiv),4-dimethylaminopyridine (3.9 g, 31.92 mmol, 1.10 equiv) and HOBT (4.3 g,31.82 mmol, 11.10 equiv) respectively in portions with stirring at 0° C.The resulting solution was stirred overnight at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 14 g (84%) of(2R)1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas a white solid. MS (ES, m/z): 569 (M+H); 1H NMR (300 MHz, CDCl₃): δ7.41-7.36 (m, 3H), 7.33-7.29 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.85 (br,2H), 5.26-5.23 (m, 1H), 5.19-5.11 (m, 2H), 5.08-4.99 (m, 0.5H),4.77-4.72 (m, 0.5H), 3.89 (br, 4H), 3.16-3.03 (m, 6H), 2.67 (d, J=8.4Hz, 3H), 1.65-1.56 (m, 3H), 1.49 (d, J=15.9 Hz, 9H), 0.92 (d, J=6.0 Hz,6H).

Preparation Example 36: Preparation of Dimer D8

Dimer D8 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (D8)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed dichloromethane (10 mL, 1.10equiv), benzyl (2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate(130 mg, 0.38 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (100 mg, 0.38 mmol, 1.00 equiv). This was followed by the additionof HOBT (57 mg, 0.42 mmol, 1.10 equiv), DCC (86 mg, 0.42 mmol, 1.10equiv) and 4-dimethylaminopyridine (51 mg, 0.42 mmol, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 180 mg (80.5%) of(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a light yellow solid. MS (ES, m/z): 587 (M+H); ¹H NMR (300 MHz,CDCl₃): δ 7.38-7.36 (m, 4H), 7.29-7.25 (m, 1H), 7.20-6.99 (m, 4H),5.27-5.18 (m, 1H), 5.18-5.09 (m, 2H), 5.08-4.83 (m, 1H), 4.01 (br, 4H),3.23 (br, 4H), 3.15-3.05 (m, 2H), 2.68 (s, 3H), 2.28-1.91 (m, 2H),1.51-1.28 (m, 15H).

Preparation Example 37: Preparation of Dimer D9

Dimer D9 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D9)

Into a 2-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tetrahydrofuran (1.5 L),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (50g, 203.82 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (36.7 g,203.66 mmol, 1.00 equiv), triphenylphosphane (85 g, 324.07 mmol, 1.50equiv). This was followed by the addition of DEAD (56.5 g, 324.43 mmol,1.20 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:50-1:10). This resulted in82 g (99%) of(2R)1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas pink oil. MS (ES, m/z): 408 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.41-7.31(m, 5H), 5.31-5.10 (m, 3H), 5.01-4.73 (m, 1H), 2.77-2.74 (m, 3H),1.72-1.65 (m, 2H), 1.60-1.58 (m, 1H), 1.52-1.50 (m, 3H), 1.47 (s, 9H),0.96-0.94 (m, 6H).

Preparation Example 38: Preparation of Dimer D10

Dimer D10 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D10)

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed tetrahydrofuran (10 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (100 mg, 0.38 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate(69 mg, 0.38 mmol, 1.00 equiv), triphenylphosphane (150 mg, 0.57 mmol,1.50 equiv). This was followed by the addition of DEAD (99 mg, 0.57mmol, 1.50 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:100-1:50). This resulted in 106 mg (66%) of(2R)1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas off-white oil. MS (ES, m/z): 426 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.41-7.32 (m, 5H), 5.23-5.10 (m, 3H), 5.09-4.82 (m, 1H), 2.80-2.77 (m,3H), 2.31-2.06 (m, 2H), 1.54-1.27 (m, 18H).

Preparation Example 39: Preparation of Dimer D11

Dimer D11 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate(D11)

Into a 1000-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(18 g, 69.41 mmol, 1.00 equiv) in tetrahydrofuran (500 mL), benzyl(2S)-2-hydroxypropanoate (12.5 g, 69.37 mmol, 1.00 equiv), PPh₃ (22 g,83.88 mmol, 1.20 equiv). This was followed by the addition of DEAD (14.5g, 83.26 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 2 h at room temperature in an ice/salt bath.The resulting mixture was concentrated under vacuum. The resultingsolution was diluted with 1000 mL of EA. The resulting mixture waswashed with 2×1000 mL of brine. The organic layer was collected anddried over anhydrous sodium sulfate. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:20-1:10). Thisresulted in 25.3 g (86%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoateas yellow oil. MS (ES, m/z): 422 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.40-7.33 (m, 5H), 5.23-4.79 (m, 4H), 2.75 (d, J=8.4 Hz, 3H), 1.85-1.61(m, 2H), 1.59-1.52 (m, 3H), 1.47 (s, 9H), 0.95 (s, 9H).

Preparation Example 40: Preparation of Dimer D12

Dimer D12 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (D12)

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (1.2 g, 4.56 mmol, 1.00 equiv) in dichloromethane (100 mL), benzyl(2R)-2-hydroxy-3-phenylpropanoate (1.17 g, 4.57 mmol, 1.00 equiv). Thiswas followed by the addition of DCC (1.13 g, 5.48 mmol, 1.20 equiv),HOBT (740 mg, 5.48 mmol, 1.20 equiv) and 4-dimethylaminopyridine (670mg, 5.48 mmol, 1.20 equiv) respectively in portions with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 1.52 g (66%) of (2R)1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 502 (M+H).

Preparation Example 41: Preparation of Dimer D13

Dimer D13 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate(D13)

Into a 250-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(3.8 g, 14.65 mmol, 1.00 equiv), benzyl(2R)2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (5 g, 14.65 mmol,1.00 equiv), dichloromethane (20 mL). This was followed by the additionof DCC (3.3 g, 1.10 equiv), HOBT (2 g, 1.10 equiv), and4-dimethylaminopyridine (2.2 g, 1.10 equiv) respectively in portionswith stirring at 0° C. The resulting solution was stirred for 14 h atroom temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 6.5 g(76%) of (2R)1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate asa white solid. MS (ES, m/z): 583 (M+H).

Preparation Example 42: Preparation of Dimer D14

Dimer D14 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D14)

Into a 1000-mL round-bottom flask, was placed dichloromethane (200 mL),benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate(12 g, 35.46 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(10.6 g, 43.21 mmol, 1.22 equiv), HOBT (6 g, 44.40 mmol, 1.25 equiv),DCC (9 g, 43.62 mmol, 1.23 equiv), 4-dimethylaminopyridine (6 g, 49.11mmol, 1.38 equiv). The resulting solution was stirred for 2 h at roomtemperature. The solids were filtered out. The filtrate concentratedunder vacuum. The filtrate was applied onto a silica gel column withethyl acetate/petroleum ether (1:5). This resulted in 18.0 g (90%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas light yellow oil. MS (ES, m/z): 566 (M+H)

Preparation Example 43: Preparation of Dimer D15

Dimer D15 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D15)

Into a 250-mL round-bottom flask, was placed a solution of benzyl(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (5.3 g, 16.97 mmol, 1.00equiv) in dichloromethane (90 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(4.2 g, 17.12 mmol, 1.00 equiv). This was followed by the addition ofDCC (3.85 g, 18.66 mmol, 1.10 equiv), HOBT (2.52 g, 18.65 mmol, 1.10equiv) and 4-dimethylaminopyridine (2.28 g, 18.66 mmol, 1.10 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:8). Thisresulted in 10 g (crude) of(2R)1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as light yellow oil. MS (ES, m/z): 562 (M+Na).

Preparation Example 44: Preparation of Dimer D16

Dimer D16 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D16)

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (4.0 g, 11.75mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(2.94 g, 11.98 mmol, 1.00 equiv), dichloromethane (100 mL). This wasfollowed by the addition of DCC (2.72 g, 13.18 mmol, 1.10 equiv),4-dimethylaminopyridine (1.61 g, 13.18 mmol, 1.10 equiv) and HOBt (1.78g, 13.17 mmol, 1.10 equiv) respectively in portions with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:30). This resulted in 4.5 g (67%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas yellow oil. MS (ES, m/z): 568 (M+H).

Preparation Example 45: Preparation of Dimer D17

Dimer D17 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D17)

Into a 100-mL round-bottom flask, was placed a solution of benzyl(2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate (1.36 g,3.97 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-methylpentanoic acid (980mg, 3.99 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followedby the addition of DCC (900 mg, 4.36 mmol, 1.10 equiv),4-dimethylaminopyridine (540 mg, 4.42 mmol, 1.10 equiv) and HOBT (740mg, 5.48 mmol, 1.10 equiv) respectively in portions with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 1.2572 g (56%) of(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas a off-white solid. MS (ES, m/z): 570 (M+H); ¹H NMR (300 MHz, CDCl₃):δ 8.01 (s, 1H), 7.39-7.33 (m, 4H), 7.30-7.28 (m, 2H), 6.59-6.56 (m, 1H),5.23-5.19 (m, 1H), 5.14 (s, 2H), 5.05-4.99 (m, 0.5H), 4.78-4.73 (m,0.5H), 3.85-3.82 (m, 4H), 3.49 (br, 4H), 3.10-2.95 (m, 2H), 2.68 (d,J=10.8 Hz, 3H), 1.64-1.57 (m, 3H), 1.48 (d, J=12.9 Hz, 9H), 0.97-0.91(m, 6H).

Preparation Example 46: Preparation of Dimer D18

Dimer D18 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D18)

Into a 100-mL 3-necked round-bottom flask, was placed benzyl(2R)-3-(4-cyanophenyl)-2-hydroxypropanoate (2 g, 7.11 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(2.3 g, 9.38 mmol, 1.30 equiv), dichloromethane (40 mL). This wasfollowed by the addition of DCC (1.6 g, 7.75 mmol, 1.10 equiv),4-dimethylaminopyridine (960 mg, 7.86 mmol, 1.10 equiv) and HOBT (1.1 g,8.14 mmol, 1.10 equiv) respectively in portions with stirring at 0° C.The resulting solution was stirred for 17 h at room temperature. Thesolids were filtered out. The filtrate was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 3.3 g (91%) of(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as awhite solid. MS (ES, m/z): 509 (M+H).

Preparation Example 47: Preparation of Dimer D19

Dimer D19 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D19)

Into a 500-mL round-bottom flask, was placed dichloromethane (400 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (20 g, 75.96 mmol, 1.00 equiv), benzyl(2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate (25.8g, 76.24 mmol, 1.00 equiv). This was followed by the addition of HOBT(12 g, 88.81 mmol, 1.15 equiv), DCC (18 g, 87.24 mmol, 1.15 equiv) and4-dimethylaminopyridine (10.7 g, 87.58 mmol, 1.15 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirred for 4h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10-1:5). This resulted in80 g (90%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 584 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.37-7.16 (m, 7H), 7.14 (d, J=8.4 Hz, 2H), 6.12 (s, 1H), 5.28-5.25 (m,1H), 5.15-5.13 (m, 2H), 5.12-4.81 (m, 1H), 4.35-4.33 (m, 2H), 3.95 (t,J=8.7 Hz, 2H), 3.18-3.14 (m, 2H), 2.68 (d, J=12.9 Hz, 3H), 2.53-2.49 (m,2H), 2.22-2.10 (m, 1H), 2.06-1.85 (m, 1H), 1.48 (d, J=16.8 Hz, 9H), 1.39(s, 3H), 1.32 (s, 3H).

Preparation Example 48: Preparation of Dimer D20

Dimer D20 was prepared by the process shown in Scheme 29 below.

Experimental Details

2-bromo-5-(3,6-dihydro-2H-pyran-4-yl)pyridine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dioxane (2 mL), water (1 mL),2-bromo-5-iodopyridine (100 mg, 0.35 mmol, 1.00 equiv),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(104 mg, 0.50 mmol, 1.30 equiv), potassium carbonate (120 mg, 0.86 mmol,3.00 equiv), Pd(PPh₃)₄(40 mg, 0.03 mmol, 0.10 equiv). The resultingsolution was stirred overnight at 80° C. in an oil bath. The reactionmixture was cooled and concentrated under vacuum. The residue waspurified by preparative TLC (EtOAc:PE=1:1). This resulted in 50 mg (59%)of 2-bromo-5-(3,6-dihydro-2H-pyran-4-yl)pyridine as colorless oil. MS(ES, m/z): 240 (M+H).

(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-ol

Into a 250-mL 3-necked round-bottom flask, was placed tetrahydrofuran(200 mL), 2-bromo-5-(3,6-dihydro-2H-pyran-4-yl)pyridine (4 g, 16.66mmol, 1.00 equiv). This was followed by the addition of butyllithium(8.7 mL, 1.30 equiv) dropwise with stirring at −78° C. To this was addedBF₃.Et₂O (2.8 mL, 1.00 equiv) at −78° C. To the mixture was added asolution of (2R)-2-[(benzyloxy)methyl]oxirane (3.6 g, 21.92 mmol, 1.30equiv) in tetrahydrofuran (10 mL) at −78° C. The resulting solution wasstirred for 1.5 h at −78° C. The reaction was then quenched by theaddition of 100 mL of NH₄Cl (aq). The resulting solution was extractedwith 3×100 mL of ethyl acetate and the organic layers combined. Theorganic layer was washed with 3×50 mL of brine. The organic layer wascollected and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 2 g (37%) of(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-olas a yellow solid. MS (ES, m/z): 326 (M+H).

(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed dichloromethane (50 mL),(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-ol(1.84 g, 5.65 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (3.4 g, 12.91 mmol, 2.50 equiv). This was followed by the additionof 4-dimethylaminopyridine (1.4 g, 11.46 mmol, 2.00 equiv), HOBT (1.5 g,47.11 mmol, 2.00 equiv) and DCC (2.3 g, 85.05 mmol, 2.00 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 4.0 gof(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a yellow solid. MS (ES, m/z): 571 (M+H).

(2R)-1-hydroxy-3-[5-(oxan-4-yl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 250-mL round-bottom flask, was placed Pd(OH)₂/C (4 g),(2R)-1-(benzyloxy)-3-[5-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(4 g, 7.01 mmol, 1.00 equiv). This was followed by the addition of ethylacetate (100 mL). To the above hydrogen was introduced. The resultingsolution was stirred for 8 h at room temperature. The solid was filteredout. The filtrate was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 800 mg of(2R)-1-hydroxy-3-[5-(oxan-4-yl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a brown solid. MS (ES, m/z): 483 (M+H).

(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-(5-tetrahydropyran-4-yl-2-pyridyl)propanoicacid

Into a 8-mL vial, was placed(2R)-1-hydroxy-3-[5-(oxan-4-yl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (20 mg, 0.04 mmol, 1.00 equiv), CH₃CN(1 mL), chloroform (1 mL), water (2 mL), sodium periodate (44 mg, 0.21mmol, 5.00 equiv), trichlororuthenium (1 mg, 0.10 equiv). The resultingsolution was stirred for 2 h at room temperature. MS (ES, m/z): 497(M+H).

Preparation Example 49: Preparation of Dimer D21

Dimer D21 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D21)

Into a 50-mL round-bottom flask, was placed benzyl(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate (500 mg,1.54 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(489.9 mg, 2.00 mmol, 1.30 equiv), 4-dimethylaminopyridine (206.4 mg,1.69 mmol, 1.10 equiv), HOBT (230.1 mg, 1.70 mmol, 1.11 equiv),dichloromethane (10 mL). This was followed by the addition of DCC (348.5mg, 1.69 mmol, 1.10 equiv) in portions at 0° C. The resulting solutionwas stirred for 12 h at 0-25° C. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 281.2 mg (33%) of(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate aslight yellow oil. MS (ES, m/z): 553 (M+H).

Preparation Example 50: Preparation of Dimer D22

Dimer D22 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[6-(oxan-4-yl)pyridin-3-yl]-1-oxopropan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D22)

Into a 50-mL round-bottom flask, was placed tetrahydrofuran (5 mL),benzyl (2S)-2-hydroxy-3-[6-(oxan-4-yl)pyridin-3-yl]propanoate (900 mg,2.64 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (1.1 g, 4.18 mmol, 1.58 equiv), PPh3 (1.7 g, 6.48 mmol, 2.46equiv), DEAD (1.3 g, 7.46 mmol, 2.83 equiv). The resulting solution wasstirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 1.7 gof(2R)-1-(benzyloxy)-3-[6-(oxan-4-yl)pyridin-3-yl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a white solid. MS (ES, m/z): 587 (M+H); ¹HNMR (300 MHz, CDCl₃): δ8.38 (s, 1H), 7.50-7.49 (br, 1H), 7.37-7.31 (m, 5H), 7.12 (br, 1H),5.32-5.12 (m, 3H), 4.92-4.63 (m, 1H), 4.13-4.09 (m, 2H), 3.61-3.56 (m,2H), 3.17-3.16 (m, 2H), 2.98 (br, 1H), 2.74-2.66 (m, 3H), 2.29-1.96 (m,2H), 1.87-1.85 (4H), 1.51-1.27 (m, 15)

Preparation Example 51: Preparation of Dimer D23

Dimer D23 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D23)

Into a 50-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (526 mg, 2.00 mmol, 1.30 equiv), benzyl(2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate (500 mg,1.54 mmol, 1.00 equiv), dichloromethane (10 mL). This was followed byaddition of 4-dimethylaminopyridine (206.4 mg, 1.69 mmol, 1.10 equiv),HOBT (230.1 mg, 1.70 mmol, 1.10 equiv) and DCC (348.6 mg, 1.69 mmol,1.10 equiv) respectively in several batches at 0° C. The resultingsolution was stirred for 12 h at 25° C. The solids were filtered out.The filtrate was concentrated under vacuum. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:5). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 305 mg (27%) of(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate as light yellow oil.MS (ES, m/z): 571 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 8.75 (s, 1H),7.86-7.82 (m, 1H), 7.38-7.28 (m, 6H), 5.63-5.58 (m, 1H), 5.31-5.17 (m,2H), 5.12-4.71 (m, 1H), 3.48-3.45 (m, 2H), 2.69 (d, J=11.7 Hz, 2H),2.29-1.83 (m, 2H), 1.45-1.27 (m, 15H).

Preparation Example 52: Preparation of Dimer D24

Dimer D24 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl(2S)-2-[[(tert-(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (D24)

Into a 100-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (5.2 g, 19.75 mmol, 1.00 equiv), benzyl(2R)-3-(4-cyanophenyl)-2-hydroxypropanoate (4.25 g, 15.11 mmol, 1.30equiv), dichloromethane (40 mL). This was followed by the addition ofDCC (3.4 g, 16.48 mmol, 1.10 equiv), 4-dimethylaminopyridine (2 g, 16.37mmol, 1.10 equiv) and HOBt (2.2 g, 16.28 mmol, 1.10 equiv) respectivelyin portions with stirring at 0° C. The resulting solution was stirredfor 17 h at room temperature. The solids were filtered out. The filtratewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 3.2 g(31%) of(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas a white solid. MS (ES, m/z): 527 (M+H).

Preparation Example 53: Preparation of Dimer D25

Dimer D25 was prepared by the the reaction shown below.

2-(Benzyloxy)-2-oxoethyl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (D25)

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of benzyl2-hydroxyacetate (3.5 g, 21.06 mmol, 1.00 equiv), dichloromethane (100mL), (2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-methylpentanoic acid(5.2 g, 21.20 mmol, 1.00 equiv). This was followed by the addition ofDCC (5.21 g, 25.25 mmol, 1.20 equiv), HOBT (3.42 g, 25.31 mmol, 1.20equiv) and 4-dimethylaminopyridine (3.1 g, 25.37 mmol, 1.20 equiv)respectively in portions with stirring at 0° C. The resulting solutionwas stirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:20-1:5). This resulted in5.3 g (64%) of 2-(benzyloxy)-2-oxoethyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate ascolorless oil. MS (ES, m/z): 394 (M+H).

Preparation Example 54: Preparation of Dimer D26

Dimer D26 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D26)

Into a 250-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(900 mg, 3.67 mmol, 1.00 equiv), dichloromethane (30 mL), benzyl(2S)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-2-hydroxypropanoate (620 mg, 1.73mmol, 1.00 equiv). This was followed by the addition of DCC (570 mg,2.76 mmol, 1.10 equiv), HOBT (373 mg, 2.76 mmol, 1.10 equiv) and4-dimethylaminopyridine (340 mg, 2.78 mmol, 1.10 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:5). This resulted in 1.2 g (56%) of(2R)1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas colorless oil. MS (ES, m/z): 586 (M+H).

Preparation Example 55: Preparation of Dimer D27

Dimer D27 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate (1.5g, 4.15 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (1g, 4.08 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed bythe addition of DCC (1.1 g, 5.33 mmol, 1.20 equiv),4-dimethylaminopyridine (600 mg, 4.91 mmol, 1.20 equiv) and HOBT (700mg, 5.18 mmol, 1.20 equiv) respectively in portions with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:15). Thisresulted in 1.7 g (70%) of(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas yellow oil. MS (ES, m/z): 589 (M+H).

Preparation Example 56: Preparation of Dimer D28

Dimer D28 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D28)

Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (700 mg, 2.66 mmol, 1.00 equiv), DCM (30 mL), benzyl(2S)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-2-hydroxypropanoate (513 mg, 1.43mmol, 1.00 equiv). This was followed by the addition of HOBT (262 mg,1.94 mmol, 1.10 equiv), DCC (442 mg, 2.14 mmol, 1.10 equiv) and4-dimethylaminopyridine (290 mg, 2.37 mmol, 1.10 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 850 mg (53%) of(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate as colorless oil. MS(ES, m/z): 604 (M+H).

Preparation Example 57: Preparation of Dimer D29

Dimer D29 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D29)

Into a 1000-mL 3-necked round-bottom flask, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (25 g, 94.95 mmol, 1.00 equiv) in dichloromethane (1000 mL), benzyl(2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (30 g, 96.03 mmol, 1.00equiv), DCC (40 g, 193.86 mmol, 2.00 equiv), HOBT (26 g, 192.42 mmol,2.00 equiv), 4-dimethylaminopyridine (23.5 g, 192.35 mmol, 2.00 equiv).The resulting solution was stirred for 2 h at room temperature in anice/salt bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:50-1:10). This resulted in 50 g (94%) of(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 558 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.35-7.27 (m, 7H), 7.12-7.09 (m, 2H), 5.27-4.62 (m, 4H), 3.15-3.09 (m,2H), 2.69-2.61 (m, 3H), 2.20-1.82 (m, 2H), 1.61-1.31 (m, 24H).

Preparation Example 58: Preparation of Dimer D30

Dimer D30 was prepared by the the reaction shown below.

[(1R)-1-benzyl-2-benzyloxy-2-oxo-ethyl]-(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoate(D30)

To a stirred solution ofN-tert-butoxycarbonyl-N-methyl-gamma-methyl-L-leucine (0.8 g, 3.1 mmol),benzyl R-2-hydroxy-3-phenylpropionate (0.8 g, 3.1 mmol) and DMAP (cat.)in 8 mL DCM cooled to 0° C. was added EDAC (1.0 g, 4.6 mmol) and themixture stirred overnight allowing it to warm to room temperature. Themixture was diluted with 70 ml DCM, washed with 70 mL water, dried oversodium sulfate, filtered, concentrated and the residue purified onsilica gel column eluting with ethyl acetate/heptanes to obtain thetarget compound as a white solid. Yield: 1.46 g, 95%. ¹H NMR (DMSO-d₆):δ 7.28 (m, 10H), 5.28 (m, 1H), 5.12 (d, J=6.1 Hz, 2H), 4.89 (m, 0.5H),4.63 (m, 0.5H), 3.17 (m, 1H), 3.07 (m, 1H), 2.54 (m, 3H), 1.50 (m, 2H),1.41 (s, 5H), 1.35 (s, 4H).

Preparation Example 59: Preparation of Dimer D31

Dimer D31 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoate(D31)

Into a 8-mL round-bottom flask, was placed dichloromethane (4 mL),(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoicacid (200 mg, 0.42 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (173 mg, 0.51mmol, 1.20 equiv). This was followed by the addition of HOBT (70 mg,0.52 mmol, 1.20 equiv), DCC (104 mg, 0.50 mmol, 1.20 equiv) and4-dimethylaminopyridine (62 mg, 0.51 mmol, 1.20 equiv) respectively inportions with stirring at 0° C. The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by preparative TLC (EtOAc:PE=1:3). Thisresulted in 177 mg (53%) of(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-5,5,5-trifluoro-4-(trifluoromethyl)pentanoateas a off-white solid. MS (ES, m/z): 799 (M+H); ¹H NMR (300 MHz, CDCl₃):δ 7.81-7.78 (m, 2H), 7.65-7.60 (m, 2H), 7.48-7.28 (m, 11H), 7.10-7.00(m, 2H), 5.29-5.26 (m, 1H), 5.21-5.17 (m, 2H), 5.13-4.94 (m, 1H),4.60-4.50 (m, 3H), 4.32-4.18 (m, 1H), 4.01 (br, 4H), 3.20-3.07 (m, 6H),2.70 (s, 3H), 2.45-2.33 (m, 1H), 2.14-1.96 (m, 1H).

Preparation Example 60: Preparation of Dimer D32

Dimer D32 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanoate(D32)

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tetrahydrofuran (100 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanoic acid (5 g, 24.60mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (4.43 g, 24.58 mmol,1.00 equiv), PPh₃ (8.4 g, 32.03 mmol, 1.30 equiv). This was followed bythe addition of DEAD (5.6 g, 32.16 mmol, 1.30 equiv) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:30-1:15). This resulted in 9 g (100%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]propanoate as colorlessoil. MS (ES, m/z): 366 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 7.42-7.32 (m,5H), 5.24-5.12 (m, 3H), 5.03-4.69 (m, 1H), 2.83-2.79 (m, 3H), 1.53-1.39(m, 15H).

Preparation Example 61: Preparation of Dimer D33

Dimer D33 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylbutanoate(D33)

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylbutanoic acid (2g, 8.65 mmol, 1.00 equiv), tetrahydrofuran (80 mL), benzyl(2S)-2-hydroxypropanoate (1.6 g, 8.88 mmol, 1.00 equiv), PPh₃ (4.6 g,17.54 mmol, 2.00 equiv). This was followed by the addition of DEAD (3 g,17.23 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1/9). This resulted in 3.3 g(97%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylbutanoateas a pink liquid. MS (ES, m/z): 394 (M+H).

Preparation Example 62: Preparation of Dimer D34

Dimer D34 was prepared by the the reaction shown below.

2-(Benzyloxy)-2-oxoethyl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate (D34)

Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoic acid(1 g, 3.86 mmol, 1.00 equiv), benzyl 2-hydroxyacetate (770 mg, 4.63mmol, 1.20 equiv), dichloromethane (25 mL). This was followed by theaddition of DCC (950 mg, 4.60 mmol, 1.20 equiv), HOBt (630 mg, 4.66mmol, 1.20 equiv) and 4-dimethylaminopyridine (570 mg, 4.67 mmol, 1.20equiv) respectively in portions with stirring at 0° C. The resultingsolution was stirred for 2 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:9). This resulted in 1.15 g (73%) of2-(benzyloxy)-2-oxoethyl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4,4-dimethylpentanoate as colorless oil. MS (ES, m/z): 408 (M+H); ¹HNMR (300 MHz,CDCl₃): δ 7.40-7.34 (m, 5H), 5.20 (s, 2H), 5.09-4.71 (m, 1H), 4.70-4.68(m, 2H), 2.81-2.79 (m, 3H), 1.93-1.88 (m, 1H), 1.71-1.66 (m, 1H), 1.47(s, 9H), 0.94 (s, 9H).

Preparation Example 63: Preparation of Dimer D36

Dimer D36 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3,3-dimethylbutanoate(D36)

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3,3-dimethylbutanoic acid(1.5 g, 6.11 mmol, 1.00 equiv), tetrahydrofuran (40 mL), benzyl(2S)-2-hydroxypropanoate (1.1 g, 6.10 mmol, 1.00 equiv), PPh₃ (1.92 g,7.32 mmol, 1.20 equiv). This was followed by the addition of DEAD (1.27g, 7.29 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 2 g (80%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3,3-dimethylbutanoate aslight yellow oil. MS (ES, m/z): 408 (M+H).

Preparation Example 64: Preparation of Dimer D37

Dimer D37 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]pentanoate(D37)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl) amino]pentanoic acid (800 mg,3.46 mmol, 1.00 equiv), tetrahydrofuran (60 mL), benzyl(2S)-2-hydroxypropanoate (623 mg, 3.46 mmol, 1.00 equiv), PPh₃ (1.8 g,6.86 mmol, 1.99 equiv). This was followed by the addition of DEAD (1.20g, 6.89 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1/9). This resulted in 1.05 g(77%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]pentanoateas a colorless liquid. MS (ES, m/z): 394 (M+H).

Preparation Example 65: Preparation of Dimer D38

Dimer D38 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylpentanoate(D38)

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylpentanoic acid (4g, 16.31 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (3.2 g,17.76 mmol, 1.09 equiv), tetrahydrofuran (100 mL), PPh₃ (5.3 g, 20.21mmol, 1.24 equiv). This was followed by the addition of DEAD (4.1 g,23.54 mmol, 1.44 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 4 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:5). This resulted in 4.2 g(63%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methylpentanoateas yellow oil. MS (ES, m/z): 408 (M+H).

Preparation Example 66: Preparation of Dimer D40

Dimer D40 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(4-fluorophenyl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (D40)

Into a 100-mL round-bottom flask, was placed a solution of(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (1.2 g, 4.56 mmol, 1.00 equiv), dichloromethane (30 mL), benzyl(2R)3-[4-(4-fluorophenyl)phenyl]-2-hydroxypropanoate (900 mg, 2.57 mmol,1.00 equiv). This was followed by the addition of4-dimethylaminopyridine (500 mg, 4.09 mmol, 1.10 equiv), DCC (780 mg,3.78 mmol, 1.10 equiv) and HOBT (510 mg, 3.77 mmol, 1.10 equiv)respectively in portions at 0° C. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 2 g (74%) of(2R)-1-(benzyloxy)-3-[4-(4-fluorophenyl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 596 (M+H).

Preparation Example 67: Preparation of Dimer D41

Dimer D41 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D41)

Into a 100-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (542 mg, 2.06 mmol, 1.00 equiv), benzyl(2R)3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate(750 mg, 2.06 mmol, 1.00 equiv), dichloromethane (60 mL). This wasfollowed by the addition of DCC (467 mg, 2.26 mmol, 1.10 equiv),4-dimethylaminopyridine (276 mg, 2.26 mmol, 1.10 equiv) and HOBt (306mg, 2.26 mmol, 1.10 equiv) respectively in portions at 0° C. Theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:20). Thisresulted in 850 mg (68%) of(2R)-1-(benzyloxy)-3-[4-(4,4-dimethylcyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 610 (M+H).

Preparation Example 68: Preparation of Dimer D42

Dimer D42 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoate(D42)

Into a 50-mL round-bottom flask, was placed tetrahydrofuran (20 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoicacid (1 g, 2.98 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (530mg, 2.94 mmol, 1.00 equiv), PPh₃ (1 g, 3.81 mmol, 1.30 equiv). This wasfollowed by the addition of DEAD (670 mg, 3.85 mmol, 1.30 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:5). This resulted in 1.4 g (94%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-tert-butylphenyl)propanoateas colorless oil. MS (ES, m/z): 498 (M+H).

Preparation Example 69: Preparation of Dimer D43

Dimer D43 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoate(D43)

Into a 50-mL round-bottom flask, was placed tetrahydrofuran (10 mL),benzyl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoate(1 g, 2.24 mmol, 1.00 equiv), benzyl-(2S)-2-hydroxypropanoate (760 mg,4.22 mmol, 1.88 equiv), PPh₃ (1.5 g, 5.72 mmol, 2.55 equiv). This wasfollowed by the addition of DEAD (960 mg, 5.51 mmol, 2.46 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 1.1 g (91%) of(2R)-1-(benzyloxy)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-(4-phenylphenyl)propanoateas colorless oil. MS (ES, m/z): 518 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.58-7.30 (m, 14H), 5.27-5.15 (m, 3H), 4.96-4.91 (m, 1H), 3.36-3.30 (m,1H), 3.06-2.82 (m, 1H), 2.78-2.71 (m, 3H), 1.55-1.52 (m, 3H), 1.46-1.22(m, 12H).

Preparation Example 70: Preparation of Dimer D44

Dimer D44 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)naphthalen-1-yl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D44)

Into a 100-mL round-bottom flask, was placed benzyl(2R)-2-hydroxy-3-[4-(morpholin-4-yl)naphthalen-1-yl]propanoate (600 mg,1.53 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (600 mg, 2.28 mmol, 1.49 equiv), dichloromethane (20 mL).

This was followed by the addition of HOBt (410 mg, 3.03 mmol, 1.98equiv), 4-dimethylaminopyridine (370 mg, 3.03 mmol, 1.98 equiv) and DCC(470 mg, 2.28 mmol, 1.49 equiv) respectively in portions with stirringat 0° C. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 600 mg (61%) of(2R)-1-(benzyloxy)-3-[4-(morpholin-4-yl)naphthalen-1-yl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 637 (M+H).

Preparation Example 71: Preparation of Dimer D45

Dimer D45 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D45)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed tetrahydrofuran (25 mL), benzyl(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoate (710mg, 2.00 mmol, 1.00 equiv), (2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoic acid (527 mg, 2.00mmol, 1.00 equiv), PPh₃ (790 mg, 3.01 mmol, 1.50 equiv). This wasfollowed by the addition of DEAD (517 mg, 2.97 mmol, 1.50 equiv)dropwise with stirring at 0° C. The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated undervacuum. The residue was purified by thin layer chromatography developedwith ethyl acetate/PE (1/5). This resulted in 710 mg (59%) of(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 600 (M+H).

Preparation Example 72: Preparation of Dimer D46

Dimer D46 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D46)

Into a 100-mL round-bottom flask, was placed dichloromethane (50 mL),benzyl(2R)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-2-hydroxypropanoate (2g, 5.37 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (1.42 g, 5.39 mmol, 1.10 equiv). This was followed by the additionof HOBT (870 mg, 6.44 mmol, 1.20 equiv), in portions. To this was addedDCC (1.33 g, 6.45 mmol, 1.20 equiv), in portions. To the mixture wasadded 4-dimethylaminopyridine (780 mg, 6.38 mmol, 1.20 equiv), inportions. The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:20-1:15). This resulted in 3.2 g (96%) of(2R)-1-(benzyloxy)-3-[4-(4,4-difluorocyclohex-1-en-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 618 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.36-7.34 (m, 5H), 7.26-7.25 (m, 2H), 7.14-7.11 (m, 2H), 5.89 (br, 1H),5.29-5.23 (m, 1H), 5.18-5.06 (m, 2H), 4.89-4.78 (m, 1H), 3.17-3.10 (m,2H), 2.77-2.65 (m, 7H), 2.23-1.97 (m, 2H), 1.59-1.15 (m, 17H).

Preparation Example 73: Preparation of Dimer D47

Dimer D47 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D47)

Into a 250-mL 3-necked round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (3.1 g, 11.77 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (4 g, 11.75mmol, 1.00 equiv), dichloromethane (120 mL).

This was followed by the addition of DCC (2.7 g, 13.09 mmol, 1.10equiv), 4-dimethylaminopyridine (1.6 g, 13.10 mmol, 1.10 equiv) and HOBt(1.7 g, 12.58 mmol, 1.10 equiv) respectively in portions with stirringat 0° C. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:10). This resulted in 3.5 g (51%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas yellow oil. MS (ES, m/z): 586 (M+H); ¹H NMR (300 MHz, CDCl₃): δ7.39-7.37 (m, 4H), 7.28-7.26 (m, 1H), 7.19-7.08 (m, 4H), 5.30-5.27 (m,1H), 5.22-5.10 (m, 2H), 5.05-4.82 (m, 1H), 3.19-3.16 (m, 2H), 2.66 (d,J=22.5 Hz, 3H), 2.28-2.16 (m, 1H), 2.07-1.92 (m, 1H), 1.51-1.33 (m,15H).

Preparation Example 74: Preparation of Dimer D48

Dimer D48 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D48)

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzyl(2S)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-hydroxypropanoate(700 mg, 1.96 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (776 mg, 2.95 mmol, 1.50 equiv), PPh₃ (1.03 g, 3.93 mmol, 2.00equiv), tetrahydrofuran (50 mL). This was followed by the addition ofDEAD (684 mg, 3.93 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/4). Thisresulted in 950 mg (80%) of(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas light yellow oil. MS (ES, m/z): 602 (M+H); ¹H NMR (300 MHz, CD₃OD): δ7.36-7.28 (m, 5H), 7.14-7.12 (m, 1H), 6.97-6.93 (m, 2H), 6.03 (br, 1H),5.33-5.31 (m, 1H), 5.17-5.12 (m, 2H), 4.93-4.90 (m, 0.5H), 4.73-4.56 (m,0.5H), 4.34-4.23 (m, 2H), 3.88-3.83 (m, 2H), 3.15-3.12 (m, 2H),2.75-2.71 (m, 3H), 2.50 (br, 2H), 2.31-1.97 (m, 2H), 1.47-1.23 (m, 15H).

Preparation Example 75: Preparation of Dimer D49

Dimer D49 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D49)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed tetrahydrofuran (25 mL), benzyl(2S)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-2-hydroxypropanoate (710mg, 2.00 mmol, 1.00 equiv),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (527 mg, 2.00 mmol, 1.00 equiv), PPh₃ (790 mg, 3.01 mmol, 1.50equiv). This was followed by the addition of DEAD (517 mg, 2.97 mmol,1.50 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was purified by thin layerchromatography developed with ethyl acetate/PE (1/5). This resulted in710 mg (59%) of(2R)-1-(benzyloxy)-3-[4-(cyclohex-1-en-1-yl)-3-fluorophenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas colorless oil. MS (ES, m/z): 600 (M+H); ¹HNMR (300 MHz, CDCl₃): δ7.35-7.27 (m, 5H), 7.15-7.11 (m, 1H), 6.87-6.82 (m, 2H), 5.91 (br, 1H),5.30-5.06 (m, 3H), 4.94-4.65 (m, 1H), 3.14-3.10 (m, 2H), 2.74-2.68 (m,3H), 2.22-1.96 (m, 2H), 1.80-1.70 (m, 4H), 1.69-1.25 (m, 19H).

Preparation Example 76: Preparation of Dimer D50

Dimer D50 was prepared by the process shown in Scheme 30 below.

Experimental Details

(2S)-1-(benzyloxy)-3-fluoropropan-2-ol

Into a 250-mL round-bottom flask, was placed a solution of(2R)-2-[(benzyloxy)methyl]oxirane (3 g, 18.27 mmol, 1.00 equiv) inheptane (50 mL), TBABF (15 g, 3.00 equiv), KHF₂ (3.2 g, 3.00 equiv). Theresulting solution was stirred for 5 h at 130° C. The reaction was thenquenched by the addition of 200 mL of water/ice. The resulting solutionwas extracted with 3×50 mL of ethyl acetate and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 3.1 g (92%) of(2S)-1-(benzyloxy)-3-fluoropropan-2-ol as colorless oil. ¹HNMR (300 MHz,CDCl₃): δ 7.41-7.29 (m, 5H), 4.61 (s, 2H), 4.60-4.51 (m, 1H), 4.39-4.36(m, 1H), 4.13-4.00 (m, 1H), 3.64-3.54 (m, 2H); ¹⁹F NMR (300 MHz, CDCl₃):δ 232.19

(2S)-1-(benzyloxy)-3-fluoropropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate

Into a 500-mL round-bottom flask, was placed dichloromethane (200 mL),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(14.6 g, 59.52 mmol, 1.10 equiv), (2S)-1-(benzyloxy)-3-fluoropropan-2-ol(10 g, 54.29 mmol, 1.00 equiv), DCC (14 g, 67.85 mmol, 1.25 equiv),4-dimethylaminopyridine (8 g, 65.48 mmol, 1.21 equiv), HOBT (8.8 g,65.13 mmol, 1.20 equiv). The resulting solution was stirred for 2 h atroom temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 16 g(72%) of(2S)-1-(benzyloxy)-3-fluoropropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas colorless oil. MS (ES, m/z): 412 (M+H).

(2S)-1-fluoro-3-hydroxypropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate

Into a 100-mL round-bottom flask, was placed methanol (30 mL),(2S)-1-(benzyloxy)-3-fluoropropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (7 g, 17.01 mmol, 1.00 equiv), and Palladium on carbon (2 g).To the above mixture hydrogen was introduced. The resulting solution wasstirred overnight at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 5.3 g (97%) of(2S)-1-fluoro-3-hydroxypropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoateas light yellow oil. MS (ES, m/z): 322 (M+H).

(2S)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]-3-fluoropropanoicacid (D50)

Into a 1000-mL round-bottom flask, was placed water (100 mL), chloroform(150 mL), ACN (150 mL), (2S)-1-fluoro-3-hydroxypropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (6 g,18.67 mmol, 1.00 equiv), RuCl₃ (2.1 g), NaIO₄ (20 g). The resultingsolution was stirred for 3 h at room temperature. The solids werefiltered out. The resulting solution was extracted with 3×50 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 3×60 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 4.2 g(67%) of(2S)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]-3-fluoropropanoicacid as yellow oil. MS (ES, m/z): 236 (M+H-Boc); ¹H NMR (300 MHz,CDCl₃): δ 5.42 (br, 1H), 4.92-4.63 (m, 3H), 2.85-2.82 (m, 3H), 1.83-1.53(m, 3H), 1.46 (s, 9H), 1.02-0.86 (m, 6H).

Preparation Example 77: Preparation of Dimer D51

Dimer D51 was prepared by the the reaction shown below.

(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(D51)

Into a 250-mL 3-necked round-bottom flask, was placed benzyl(2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate (1.5g, 4.15 mmol, 1.00 equiv),(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (1g, 4.08 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed bythe addition of DCC (1.1 g, 5.33 mmol, 1.20 equiv),4-dimethylaminopyridine (600 mg, 4.91 mmol, 1.20 equiv) and HOBT (700mg, 5.18 mmol, 1.20 equiv) respectively in portions with stirring at 0°C. The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:15). Thisresulted in 1.7 g (70%) of(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate asyellow oil. MS (ES, m/z): 589 (M+H).

Preparation Example 78: Preparation of Dimer D52

Dimer D52 was prepared by the the reaction shown below.

[(1R)-1-benzyl-2-benzyloxy-2-oxo-ethyl]-(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoate(D52)

To a stirred solution ofN-tert-butoxycarbonyl-N-methyl-gamma-methyl-L-leucine (0.8 g, 3.1 mmol),benzyl R-2-hydroxy-3-phenylpropionate (0.8 g, 3.1 mmol) and DMAP (cat.)in 8 mL DCM cooled to 0° C. was added EDAC (1.0 g, 4.6 mmol) and themixture stirred overnight allowing it to warm to room temperature. Themixture was diluted with 70 ml DCM, washed with 70 mL water, dried oversodium sulfate, filtered, concentrated and the residue purified onsilica gel column eluting with ethyl acetate/heptanes to obtain thetarget compound as a white solid. Yield: 1.46 g, 95%. ¹H NMR (DMSO-d₆):δ 7.28 (m, 10H), 5.28 (m, 1H), 5.12 (d, J=6.1 Hz, 2H), 4.89 (m, 0.5H),4.63 (m, 0.5H), 3.17 (m, 1H), 3.07 (m, 1H), 2.54 (m, 3H), 1.50 (m, 2H),1.41 (s, 5H), 1.35 (s, 4H).

Preparation Example 79: Preparation of Dimer D53

Dimer D53 was prepared by the the reaction shown below.

[(1R)-2-benzyloxy-1-methyl-2-oxo-ethyl]-(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoate(D53)

To a stirred solution ofN-tert-butoxycarbonyl-N-methyl-gamma-methyl-L-leucine (0.8 g, 3.1 mmol),benzyl L-lactate (0.56 g, 3.1 mmol) and triphenylphosphine (1.0 g, 3.7mmol) in 8 mL THF cooled to 0° C. was added dropwise a solution ofdiisobutylazodicarboxylate (0.76 g, 3.7 mmol) in 2 mL THF and themixture stirred overnight allowing it to warm to room temperature. Themixture was diluted with 100 mL ethyl acetate, washed with 100 mL water,washed with brine, dried over sodium sulfate and concentrated. Theresidue was purified on silica gel column eluting with ethyl acetate andheptanes to obtain the target compound as a clear oil. Yield: 1.3 g(quantitative). ¹H NMR (DMSO-d₆): δ 7.36 (m, 5H), 5.16 (s, 2H), 5.09 (m,1H), 4.90 (m, 0.5H), 4.69 (m, 0.5), 2.65 (s, 3H), 1.66 (m, 2H), 1.40 (m,12H), 0.89 (m, 9H).

Preparation Example 80: Preparation of Dimer D54

Dimer D54 was prepared by the the reaction shown below.

[(1R)-2-benzyloxy-1-[(6-morpholino-3-pyridyl)methyl]-2-oxo-ethyl]-(2S)-2-[tert-butoxy-carbonyl(methyl)amino]-4-fluoro-4-methyl-pentanoate(D54)

To a stirred solution ofN-tert-butoxycarbonyl-N-methyl-gamma-fluoro-L-leucine (0.31 g, 1.2mmol), benzyl R-2-hydroxy-3-[2-(4-morpholino)-5-pyridyl]propionate (0.4g, 1.2 mmol) and DMAP (cat.) in 5 mL DCM cooled to 0° C. was added EDAC(0.34 g, 1.8 mmol) and the mixture stirred overnight allowing it to warmto room temperature. The mixture was diluted with 50 ml DCM, washed with50 mL water, dried over sodium sulfate, filtered, concentrated and theresidue purified on silica gel column eluting with ethyl acetate andheptanes to obtain the target compound as a clear oil.

Yield: 0.56 g, 82%. MS (CI, m/z): 588 (M+H).

Preparation Example 81: Preparation of Dimer D55

Dimer D55 was prepared by the the reaction shown below.

[(1R)-2-benzyloxy-2-oxo-1-[[6-(trifluoromethyl)-3-pyridyl]methyl]ethyl]-(2S)-2-[tert-butoxy-carbonyl(methyl)amino]-4-fluoro-4-methyl-pentanoate(D55)

To a stirred solution ofN-tert-butoxy-carbonyl-N-methyl-gamma-fluoro-L-leucine (0.46 g, 1.7mmol), benzyl R-2-hydroxy-3-[2-(trifluoro-methyl)-5-pyridyl]propanoate(0.56 g, 1.7 mmol) and DMAP (cat.) in 6 mL DCM cooled to 0° C. was addedEDAC (0.51 g, 2.6 mmol) and the mixture stirred overnight allowing it towarm to room temperature. The mixture was diluted with 50 ml DCM, washedwith 50 mL water, dried over sodium sulfate, filtered, concentrated andthe residue purified on silica gel column eluting with ethyl acetate andheptanes to obtain the target compound as a clear oil. Yield: 0.80 g,81%. MS (CI, m/z): 571 (M+H); ¹H NMR (CDCl₃): δ 8.52 (s, 1H), 7.59 (m,2H), 7.37 (m, 3H), 7.26 (m, 3H), 5.33 (m, 1H), 5.12 (m, 2.5H), 4.87 (m,0.5H), 3.26 (m, 2H), 2.66 (m, 3H), 2.22 (m, 1H), 1.96 (m, 1H), 1.58 (s,2H), 1.49 (s, 4H), 1.38 (m 9H).

Preparation Example 82: Preparation of Dimer D56

Dimer D56 was prepared by the the reaction shown below.

[(1R)-2-benzyloxy-2-oxo-1-[[6-(trifluoromethyl)-3-pyridyl]methyl]ethyl]-(2S)-2-[tert-butoxy-carbonyl(methyl)amino]-4-methyl-pentanoate(D56)

To a stirred solution ofN-tert-butoxycarbonyl-N-methyl-gamma-fluoro-L-leucine (0.46 g, 1.7mmol), benzyl R-2-hydroxy-3-[2-(trifluoromethyl)-5-pyridyl]propanoate(0.56 g, 1.7 mmol) and DMAP (cat.) in 6 mL DCM cooled to 0° C. was addedEDAC (0.51 g, 2.6 mmol) and the mixture stirred overnight allowing it towarm to room temperature. The mixture was diluted with 50 ml DCM, washedwith 50 mL water, dried over sodium sulfate, filtered, concentrated andthe residue purified on silica gel column eluting with ethyl acetate andheptanes to obtain the target compound as a clear oil.

Yield: 0.80 g, 81%. MS (CI, m/z): 553 (M+H).

Preparation Example 83: Preparation of Dimer D57

Dimer D57 was prepared by the process shown in Scheme 31 below.

Experimental Details

benzyl (2S)-2-(trifluoromethylsulfonyloxy)propanoate

To a solution of benzyl (S)-lactate (3.5 g, 17.5 mmol) and 2,6-lutidine(2.0 g, 18.4 mmol) in 100 mL DCM cooled to 0° C. was added triflicanhydride (5.3 g, 18.4 mmol) and the mixture was stirred 1 h. Themixture was concentrated and the residue purified on silica gel columneluting with ethyl acetate and heptanes to obtain the target compound asa light pink oil. Yield: 3.8 g, 70%. ¹H NMR (CD₂Cl₂): δ 7.38 (m, 5H),5.29 (d, J=7.0 Hz, 1H), 5.26 (s, 2H), 1.71 (d, J=7.0 Hz, 3H); ¹⁹F NMR(CD₂Cl₂): δ 75.70 (s, 3F).

tert-butyl N-[(1S)-1-(hydroxymethyl)-3-methyl-butyl]-N-methyl-carbamate

To a solution of N-boc-N-methyl-(L) leucine (4.0 g, 16 mmol) in 20 mLTHF was added 18 mL of 1M borane-THF complex in THF and the mixturestirred 30 min. The mixture was quenched with 10 mL methanol andconcentrated. The residue was dissolved in 150 mL ethyl acetate, washedwith 100 mL water, washed with brine, dried over sodium sulfate,filtered and concentrated to obtain the target compound as a clear oil.Yield: 3.5 g, 93%. ¹H NMR (CD₂Cl₂): δ 4.19 (m, 1H), 3.50 (d, J=6.9 Hz,2H), 2.68 (s, 3H), 1.86 (m, 1H), 1.51 (m, 1H), 1.44 (s, 9H), 1.39 (m,1H), 1.1 (m, 1H), 0.92 (s, 3H), 0.91 (s, 3H).

benzyl(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4-methyl-pentoxy]propanoate(D57)

To a solution of tert-butylN-[(1S)-1-(hydroxymethyl)-3-methyl-butyl]-N-methyl-carbamate (2.8 g, 12mmol) in 35 mL THF under nitrogen atmosphere cooled to −78° C. was addeddropwise 7.6 mL of 1.6 M solution of butyllithium in THF and the mixturestirred 30 min. allowing it to warm to −20° C. The mixture was cooledback down to −78° C. and treated dropwise with a solution of benzyl(2S)-2-(trifluoromethyl-sulfonyloxy)propanoate (3.8 g, 12 mmol) in 10 mLTHF and stirred overnight allowing it to warm to room temperature. Themixture was diluted with 100 mL water and extracted into 100 mL ethylacetate. The organic layer was separated, washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified onsilica gel column eluting with ethyl acetate and heptanes to obtain thetarget compound as a clear oil. Yield: 0.35 g, 7.8%. MS (CI, m/z): 294(M+H-Boc); ¹H NMR (CD₂Cl₂): δ 7.33 (m, 5H), 5.16 (m, 1H), 4.73 (m, 3H),4.07 (m, 1H), 3.57 (m, 1H), 2.69 (m, 3H), 1.44 (m, 15H), 0.91 (m, 6H).

Preparation Example 84: Preparation of Dimer D58

Dimer D58 was prepared by the reaction shown below:

(2R)-1-(benzyloxy)-1-oxo-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(D1)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of benzyl(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate (266mg, 1.01 mmol, 1.20 eq.),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (300 mg, 0.84 mmol, 1.00 eq.), PPh₃ (442 mg, 1.68 mmol, 2.00 eq.),tetrahydrofuran (20 mL). This was followed by the addition of DEAD (293mg, 1.68 mmol, 2.00 eq.) dropwise with stirred at 0° C. The resultingsolution was stirred for 4 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3). This resulted in 395 mg(78%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas light yellow oil. MS (ES, m/z): 602 (M+H).

Preparation Example 85: Preparation of Dimer D59

Dimer D59 was prepared according to the reaction shown below:

(S)-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoate (D2)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of benzyl(2S)-2-hydroxy-3-[4-[(trifluoromethyl)sulfanyl]phenyl]propanoate (500mg, 1.4 mmol, 1.00 eq.) in dichloromethane (30 mL),(2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-fluoro-4-methylpentanoicacid (443 mg, 1.68 mmol, 1.20 eq.), DCC (347 mg, 1.68 mmol, 1.2 eq.),HOBT (228 mg, 1.68 mmol, 1.20 eq.), 4-dimethylaminopyridine (206 mg,1.68 mmol, 1.20 eq.). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 730 mg (86.5%) of(S)-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-4-fluoro-4-methylpentanoate as awhite solid. MS (ES, m/z): 602 (M+H).

Preparation Example 86: Preparation of Dimers D60 and DC60

Dimers D60 and DC60 were prepared according to the Scheme 32 shownbelow:

Experimental Details

(2S)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate

Into a 250-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (10g, 40.76 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (7.2 g,39.96 mmol, 1.00 equiv), and dichloromethane (150 mL). This was followedby the addition of DCC (10 g, 48.47 mmol, 1.20 equiv), HOBt (6.5 g,48.11 mmol, 1.20 equiv) and 4-dimethylaminopyridine (5.8 g, 47.47 mmol,1.20 equiv) in portions at 0° C. The resulting solution was stirred for8 h at 25° C. after which the solids were filtered out. The filtrate wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:10). This resulted in 15.2g (92%) of (2S)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate asbrown oil. (ES, m/z): 408 [M+H]⁺.

(2S)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]propanoicacid

Into a 250-mL round-bottom flask, was placed a solution of(2S)-1-(benzyloxy)-1-oxopropan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (10 g,24.54 mmol, 1.00 equiv) in 100 mL of ethyl acetate and palladium oncarbon (1 g). To this mixture was introduced hydrogen gas. The resultingsolution was stirred for 2 h at 25° C. and then the solids were filteredout. The filtrate was concentrated under vacuum resulting in 10 g(crude) of(2S)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]propanoicacid as brown oil. (ES, m/z): 318 [M+H]⁺.

Preparation Example 87: Preparation of Dimers D61 and DA61

Dimers D61 and DA61 were prepared according to Scheme 33 shown below anddescribed in the experimental details.

Experimental Details

(2S)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 100-mL round-bottom flask, was placed(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoicacid (10 g, 37.98 mmol, 1.00 equiv), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (12.9 g, 37.91mmol, 1.00 equiv), PPh₃ (19.9 g, 75.87 mmol, 2.00 equiv) andtetrahydrofuran (100 mL). This was followed by the addition of DEAD(15.3 g, 87.86 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 6 h at 25° C. and then concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:10). This resulted in 9.1 g (41%) of(2S)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas brown oil. (ES, m/z): 586 [M+H]⁺.

(2S)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate hydrochloride

Into a 50-mL round-bottom flask, was placed a solution of(2S)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(5 g, 8.54 mmol, 1.00 equiv) in dichloromethane (10 mL) and hydrogenchloride/dioxane (5 mL, 4 N). The resulting solution was stirred for 2 hat 25° C. and then concentrated under vacuum. This resulted in 4.8 g(crude) of(2S)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate hydrochloride as brownoil. (ES, m/z): 486 [M+H-HCl]+.

Preparation Example 88: Preparation of Dimers D62 and DA62

Dimers D62 and DA62 were prepared according to Scheme 34 shown below anddescribed in the experimental details.

Experimental Details

Ethyl2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 500-mL round-bottom flask, was placed ethyl4-fluoro-4-methyl-2-(methylamino)pentanoate (17 g, 88.89 mmol, 1.00equiv), dichloromethane (200 mL), Boc₂O (77.6 g, 355.56 mmol, 4.00equiv) and TEA (44.9 g, 443.72 mmol, 5.00 equiv). The resulting solutionwas stirred for 16 h at 25° C. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (20/1). The collectedfractions were combined and concentrated under vacuum. This resulted in24 g (93%) of ethyl2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate asyellow oil. (ES, m/z): 292 [M+H]⁺.

2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoic acid

Into a 500-mL round-bottom flask, was placed ethyl2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate (20g, 68.64 mmol, 1.00 equiv), tetrahydrofuran/H₂O (200/50 mL), LiOH.H₂O(11.55 g, 275.26 mmol, 4.00 equiv). The resulting solution was stirredfor 16 h at 25° C. The resulting solution was diluted with 100 mL ofH₂O. The pH value was adjusted to 5-6 with citric acid. The resultingsolution was extracted with 3×80 mL of ethyl acetate and the organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 14.7 g (81%) of2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoic acidas yellow oil. (ES, m/z): 264 [M+H]⁺.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl2-[[(tertbutoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate

Into a 500-mL round-bottom flask, was placed2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoic acid(10.2 g, 38.74 mmol, 1.10 equiv), dichloromethane (100 mL), benzyl(2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (12.0 g, 35.26mmol, 1.00 equiv), DCC (8.0 g, 38.77 mmol, 1.10 equiv),4-dimethylaminopyridine (4.74 g, 38.80 mmol, 1.10 equiv) and HOBt (6.56g, 48.55 mmol, 1.10 equiv). The resulting solution was stirred for 16 hat 25° C. The resulting solution was diluted with 200 mL of DCM and waswashed with 3×80 mL of H₂O. The resulting mixture was dried andconcentrated under vacuum. The crude product was diluted with CH₃CN (30mL) and purified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, silica gel; mobile phase, H₂O and CH₃CN (0%CH₃CN increasing to 100% within 25 min); Detector, UV 220 nm. Thisresulted in 10.5 g (51%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl2-[[(tertbutoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoateas light yellow oil. (ES, m/z): 586 [M+H]⁺.

(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2R)-4-fluoro-4-methyl-2-(methylamino)pentanoate

Into a 100-mL round-bottom flask, was placed(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl2-[[(tert-butoxy)carbonyl](methyl)amino]-4-fluoro-4-methylpentanoate(2.0 g, 3.42 mmol, 1.00 equiv) and dioxane/HCl (30 mL, 4 N). Theresulting solution was stirred for 2 h at 25° C. The resulting mixturewas concentrated under vacuum and the pH value of the solution wasadjusted to 8-9 with sodium bicarbonate (1 mol/L). The resultingsolution was extracted with 3×80 mL of ethyl acetate and the organiclayers were combined, concentrated, and dried in an oven under reducedpressure. This resulted in 1.6 g (96%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl4-fluoro-4-methyl-2-(methylamino)pentanoate as yellow oil. The crudeproduct (1.6 g) was purified by Chiral-Prep-HPLC with the followingconditions (SHIMADZU LC-20AT): Column, CHIRALPAK IC; mobile phase, PhaseA: n-Hexane, Phase B: Ethanol; Detector, 220 nm. This resulted in 420 mg(26%) of(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl(2R)-4-fluoro-4-methyl-2-(methylamino)pentanoate as light yellow oil.(ES, m/z): 486 [M+H]⁺.

Preparation Example 89: Preparation of Dimers D63 and DC63

Dimers D63 and DC62 were prepared according to Scheme 35 shown below anddescribed in the experimental details.

Experimental Details

(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpenta-noate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid(2.5 g, 10.19 mmol, 1.00 equiv) in tetrahydrofuran (35 mL), benzyl(2S)-2-hydroxypropanoate (1.67 g, 9.27 mmol, 1.00 equiv) and PPh₃ (2.92g, 11.15 mmol, 1.20 equiv). This was followed by the addition of DEAD(1.94 g, 11.14 mmol, 1.20 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 4 h at 25° C. and then concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:40-1:20). This resulted in 3.8 g (92%)of (2R)-1-(benzyloxy)-1-oxopropan-2-yl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate ascolorless oil. (ES, m/z): 408 [M+H]⁺.

(2R)-2-[[(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]propanoicacid

Into a 100-mL round-bottom flask, was placed a solution of(2R)-1-(benzyloxy)-1-oxopropan-2-yl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate (3.8 g,9.33 mmol, 1.00 equiv) in ethyl acetate (40 mL). The flask was evacuatedand flushed three times with nitrogen. After this process palladiumcarbon (500 mg) was added to the solution and the flask was flushed withhydrogen. The resulting solution was stirred for 3 h at 25° C. Thesolids were filtered out and the filtrate was concentrated under vacuum.This resulted in 2.8 g (95%) of(2R)-2-[[(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]propanoicacid as a colorless solid. (ES, m/z): 318 [M+H]⁺.

Preparation Example 90: Preparation of Compound 44-46/1-4

Compound 44-46/1-1 was prepared according to the process shown inSchemes 36-38 below. The compounds are numbered according to thesubstitution pattern of variables R^(a), R^(b), R¹, R², R³, R⁴, Cy¹ andCy² in formula (I) as shown in Tables 7-44 and the stereochemicalconfiguration described in Tables 1 to 5 above. Thus, for example,Compound 44-46/1-4 has the substitution pattern of compound 44-46 ofTable 44 and the stereochemical configuration shown in entry 4 of Table1.

Experimental Details

(S)-((R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)-2-((R)-2-((S)-4,4-dimethyl-2-(methylamino)pentanoyloxy)-N-methylpropanamido)-4-fluoro-4-methylpentanoatehydrochloride (TA44-46)

Into a 50-mL 1-necked round-bottom flask, was placed a solution of(S)-((R)-1-(((S)-1-((R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yloxy)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl)amino)-1-oxopropan-2-yl)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate(195 mg, 0.24 mmol, 1.00 eq.) in dichloromethane (5 mL). To the abovewas added hydrogen chloride (dioxane, 5 mL) dropwise at 0° C. Theresulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 175 mg(97%) of(S)-((R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)-2-((R)-2-((S)-4,4-dimethyl-2-(methylamino)pentanoyloxy)-N-methylpropanamido)-4-fluoro-4-methylpentanoatehydrochloride (TA44-46) as a white solid. MS (ES, m/z): 715 (M+H).

(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoicacid (TC44-46)

Into a 100-mL 1-necked round-bottom flask, was placed a solution ofTP44-46 (195 mg, 0.24 mmol, 1.00 eq.) in EA (20 mL), Palladium carbon(50 mg, 0.10 eq.). To the above H₂ (gas) was introduced in. Theresulting solution was stirred for 1 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 172 mg (99%) of TC44-46 as a white solid. MS (ES, m/z): 725(M+H).

[(1R)-2-[[(1S)-1-[(1R)-2-benzyloxy-2-oxo-1-[[4-(trifluoromethylsulfanyl)phenyl]methyl]ethoxy]carbonyl-3-fluoro-3-methyl-butyl]-methyl-amino]-1-methyl-2-oxo-ethyl](2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-methyl-amino]-4,4-dimethyl-pentanoate(OP44-46)

Into a 100-mL 3-necked round-bottom flask was placed a solution ofTC44-46 (172 mg, 0.24 mmol, 1.00 eq.), TA44-46 (175 mg, 0.24 mmol, 1.00eq.), BOP-Cl (121 mg, 0.47 mmol, 2.00 eq.), dichloromethane (20 mL).This was followed by the addition of DIEA (123 mg, 0.95 mmol, 4.00 eq.)dropwise with stirred at 0° C. The resulting solution was stirred for 4h at room temperature. The resulting mixture was concentrated undervacuum. The crude product was further purified by Flash-Prep-HPLC withthe following conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, water/CH₃CN=100/0 increasing to water/CH₃CN=0/100 within 25 min;Detector, UV 254 &220 nm. This resulted in 178 mg (53%) of OP44-46 as awhite solid. MS (ES, m/z): 1422 (M+H).

(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-methyl-amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoicacid (OC44-46)

Into a 100-mL round-bottom flask, was placed a solution of OP44-46 (160mg, 0.11 mmol, 1.00 eq.) in EA (20 mL), Palladium carbon (50 mg), to theabove H₂ (gas) (enough) was introduced in. The resulting solution wasstirred for 1 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum. This resulted in 145 mg (96%) ofOC44-46 as a white solid. MS (ES, m/z): 1332 (M+H).

(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2R)-2-[(2S)-4,4-dimethyl-2-(methylamino)pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-methyl-amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoicacid hydrochloride (OAC44-46)

Into a 50-mL round-bottom flask, was placed a solution of OC44-46 (145mg, 0.11 mmol, 1.00 eq.) in dichloromethane (8 mL). To the above wasadded hydrogen chloride (dioxane, 4 mL) dropwise with stirred at 0° C.The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 135 mg(97%) of OAC44-46 as a white solid. MS (ES, m/z): 1231 (M+H).

(3S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-dineopentyl-12,24-bis(4-(trifluoromethylthio)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(44-46 natural configuration)

Into a 500-mL 1-necked round-bottom flask was placed a solution ofOAC44-46 (135 mg, 0.11 mmol, 1.00 eq.) in dichloromethane (200 mL) andBOP-Cl (112 mg, 0.44 mmol, 4.00 eq.). This was followed by the additionof DIEA (84.6 mg, 0.66 mmol, 6.00 eq.) dropwise with stirred at 0° C.The resulting solution was stirred for overnight at room temperature.The resulting mixture was concentrated under vacuum. The crude productwas purified by Flash-Prep-HPLC with the following conditions(CombiFlash-1): Column, C18 silica gel; mobile phase, CH₃CN/H₂O=50%increasing to CH₃CN/H₂O=85% within 30 min; Detector, UV 220 nm. Thisresulted in 48 mg (37%) of (3 S,6R,9S,12R,15S,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-dineopentyl-12,24-bis(4-(trifluoromethylthio)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(44-46 natural configuration) as a white solid. MS (ES, m/z): 1213(M+H); ¹H NMR (300 MHz, CDCl₃, ppm): δ 7.62-7.57 (m, 4H), 7.35-7.28 (m,4H), 5.80-5.33 (br, 8H), 3.28-2.70 (m, 16H), 2.22-1.90 (m, 6H),1.64-1.12 (m, 19H), 1.11-0.02 (m, 19H); [α]=−39.82°, T=27.2° C., C=0.11g/100 mL in MeOH.

Preparation Example 91: Preparation of Compound 44-46/1-3

Compound 44-46/1-3 was prepared according to the process shown inSchemes 39-41 below.

Experimental Details

(S)-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)2-((R)-2-((S)-4,4-dimethyl-2-(methylamino)pentanoyloxy)-N-methylpropanamido)-4-fluoro-4-methylpentanoatehydrochloride (TA44-46/1-3)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of(S)-((R)-1-(((S)-1-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yloxy)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl)amino)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate (195 mg,0.24 mmol, 1.00 eq.) in dichloromethane (5 mL). To the above was addedhydrogen chloride (dioxane, 5 mL). The resulting solution was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 175 mg (crude) of(S)-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)2-((R)-2-((S)-4,4-dimethyl-2-(methylamino)pentanoyloxy)-N-methylpropanamido)-4-fluoro-4-methylpentanoatehydrochloride as a white solid. MS (ES, m/z): 715 (M+H).

(6S,9R,12S,15S)-12-(2-fluoro-2-methylpropyl)-2,2,5,9,11-pentamethyl-6-neopentyl-4,7,10,13-tetraoxo-15-(4-(trifluoromethylthio)benzyl)-3,8,14-trioxa-5,11-diazahexadecan-16-oicacid (TC44-46/1-3)

Into a 100-mL 3-necked round-bottom flask, was placed a solution of(S)-((R)-1-(((S)-1-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yloxy)-4-fluoro-4-methyl-1-oxopentan-2-yl)(methyl)amino)-1-oxopropan-2-yl)2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate (195 mg,0.24 mmol, 1.00 eq.) in EA (20 mL), Palladium carbon (50 mg). To theabove H₂ (gas) was introduced in. The resulting solution was stirred for1 h at room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. This resulted in 170 mg (98%) of(6S,9R,12S,15S)-12-(2-fluoro-2-methylpropyl)-2,2,5,9,11-pentamethyl-6-neopentyl-4,7,10,13-tetraoxo-15-(4-(trifluoromethylthio)benzyl)-3,8,14-trioxa-5,11-diazahexadecan-16-oicacid as a white solid. MS (ES, m/z): 725 (M+H).

(S)-((4S,7S,10R,13S,16S,19S,22R)-7,19-bis(2-fluoro-2-methylpropyl)-8,10,14,20-tetramethyl-13-neopentyl-3,6,9,12,15,18,21-heptaoxo-1-phenyl-4,16-bis(4-(trifluoromethylthio)benzyl)-2,5,11,17-tetraoxa-8,14,20-triazatricosan-22-yl)2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate(OP44-46/1-3)

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of(S)-((S)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethylthio)phenyl)propan-2-yl)2-((R)-2-((S)-4,4-dimethyl-2-(methylamino)pentanoyloxy)-N-methylpropanamido)-4-fluoro-4-methylpentanoatehydrochloride (175 mg, 0.23 mmol, 1.00 eq.) in dichloromethane (15 mL),(6S,9R, 12S,15S)-12-(2-fluoro-2-methylpropyl)-2,2,5,9,11-pentamethyl-6-neopentyl-4,7,10,13-tetraoxo-15-(4-(trifluoromethylthio)benzyl)-3,8,14-trioxa-5,11-diazahexadecan-16-oicacid (170 mg, 0.23 mmol, 1.00 eq.), BOP-Cl (120 mg, 0.46 mmol, 2.00eq.). To the above was added DIEA (122 mg, 0.92 mmol, 4.00 eq.) dropwisewith stirred at 0° C. The resulting solution was stirred for 4 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Flash-Prep-HPLC (C18) with H₂O/ACN (1/5).This resulted in 73 mg (22%) of (S)-((4S,7S, 1 OR, 13 S, 16S,19S,22R)-7,19-bis(2-fluoro-2-methylpropyl)-8,10,14,20-tetramethyl-13-neopentyl-3,6,9,12,15,18,21-heptaoxo-1-phenyl-4,16-bis(4-(trifluoromethylthio)benzyl)-2,5,11,17-tetraoxa-8,14,20-triazatricosan-22-yl)2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate as a whitesolid. MS (ES, m/z): 1422 (M+H).

(2S)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[[(2S)-2-[(2S)-2-[[(2R)-2-[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-methyl-amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoicacid (OC44-46/1-3)

Into a 100-mL 3-necked round-bottom flask, was placed a solution of(S)-((4S,7S, 1 OR, 13S,16S,19S,22R)-7,19-bis(2-fluoro-2-methylpropyl)-8,10,14,20-tetramethyl-13-neopentyl-3,6,9,12,15,18,21-heptaoxo-1-phenyl-4,16-bis(4-(trifluoromethylthio)benzyl)-2,5,11,17-tetraoxa-8,14,20-triazatricosan-22-yl)2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoate (73 mg, 0.05mmol, 1.00 eq.) in EA (5 mL), Palladium carbon (30 mg). To the above H₂(gas) was introduced in. The resulting solution was stirred for 1 h atroom temperature. The resulting mixture was concentrated under vacuum.This resulted in 60 mg (88%) of (OC44-46/1-3) as a white solid. MS (ES,m/z): 1332 (M+H).

(2S)-2-[(2 s)-2-[[(2R)-2-[(2S)-2-[[(2S)-2-[(2S)-2-[[(2R)-2-[(2S)-4,4-dimethyl-2-(methylamino)pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoyl]-methyl-amino]-4,4-dimethyl-pentanoyl]oxypropanoyl]-methyl-amino]-4-fluoro-4-methyl-pentanoyl]oxy-3-[4-(trifluoromethylsulfanyl)phenyl]propanoicacid hydrochloride (OAC44-46/1-3)

Into a 25-mL 3-necked round-bottom flask, was placed a solution ofOC44-46/1-3 (60 mg) in DCM (5 mL). To the above was added hydrogenchloride (dioxane, 5 mL). The resulting solution was stirred for 1 h atroom temperature. The resulting mixture was concentrated under vacuum.This resulted in 50 mg (crude) of OAC44-46/1-3 as a white solid. MS (ES,m/z): 1231 (M−H).

(3S,6R,9S,12S,15S,18R,21S,24S)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-dineopentyl-12,24-bis(4-(trifluoromethylthio)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(F2)

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of OAC44-46/1-3 (50mg) in dichloromethane (50 mL), BOP-Cl (21 mg, 2.00 eq.). This wasfollowed by the addition of DIEA (21 mg, 4.00 eq.) dropwise with stirredat 0° C. The resulting solution was stirred for 2 h at room temperature.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (waters-2767):Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water and CH₃CN(80% CH₃CN up to 90% in 8 min); Detector, UV 220 nm. This resulted in12.1 mg (20%) of (3 S,6R,9S, 12S,15 S,18R,21S,24S)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-dineopentyl-12,24-bis(4-(trifluoromethylthio)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone(44-46/1-3) as a white solid. MS (ES, m/z): 1213 (M+H); ¹H NMR (300 MHz,CDCl₃, ppm): δ 7.59-7.57 (m, 4H), 7.49-7.46 (m, 4H), 5.90-4.20 (m, 8H),3.45-3.18 (m, 4H), 3.18-2.98 (m, 5H), 2.96-2.63 (m, 2H), 2.59-2.15 (m,5H), 2.13-1.96 (m, 6H), 1.51-1.22 (m, 20H), 1.10-0.82 (m, 18H);[α]=28.860, T=27.2° C., C=0.7 g/100 mL in MeOH.

Preparation Example 92: Preparation of Compound 10-18/2-4

Compound 10-18/2-4 was prepared according to the process shown inSchemes 42-44 shown below starting from dimer compounds DC63 and DA47.

Experimental Details(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate(TP10-18A)

Into a 100-mL round-bottom flask, was placed a solution of(2R)-2-[[(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]propanoicacid (2 g, 6.30 mmol, 1.00 equiv),(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl (2S)-4-fluoro-4-methyl-2-(methylamino)pentanoate hydrogen chloride (3.29g, 6.30 mmol, 1.00 equiv) and dichloromethane (30 mL). This was followedby the addition of BOP-Cl (3.22 g, 12.63 mmol, 2.00 equiv) in portionswith stirring at 0° C. To this was added DIEA (3.26 g, 25.22 mmol, 4.00equiv) dropwise at 0° C. The resulting solution was stirred for 3 h at25° C. The solids were filtered out and the filtrate was concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, X-bridge RP18, 5 um, 19*100 mm; mobilephase, water and CH₃CN (50% CH₃CN up to 100% in 15 min); Detector, UV220 nm. This resulted in 3.3 g (67%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate ascolorless oil. (ES, m/z): 785 [M+H]⁺.

(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2R)-4-methyl-2-(methylamino)pentanoate hydro-chloride (TA10-18A)

Into a 100-mL round-bottom flask, was placed a solution of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)-carbamoyl]ethyl(2R)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate((TP10-18A), 2 g, 2.55 mmol, 1.00 equiv) in dichloromethane (3 mL). Thiswas followed by the addition of HCl (g)/dioxane (20 mL, 4N) dropwisewith stirring at 0° C. The resulting solution was stirred for 3 h at 25°C. and then concentrated under vacuum. This resulted in 1.7 g (93%) of(1R)-1-[[(2S)-1-[[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)-phenyl]propan-2-yl]oxy]-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoyl]ethyl(2R)-4-methyl-2-(methylamino)pentanoate hydrochloride as colorless oil.(ES, m/z): 685 [M+H-HCl]+.

(R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethoxy)phenyl)propan-2-yl(S)-4-fluoro-2-((6S,9R,12S,15R,18R,21R)-12-(2-fluoro-2-methylpropyl)-6,18-diisobutyl-N,2,2,5,9,11,17,21-octamethyl-4,7,10,13,16,19-hexaoxo-15-(4-(trifluoromethoxy)benzyl)-3,8,14,20-tetraoxa-5,11,17-triazadocosan-22-amido)-4-methylpentanoate(OP10-18A)

Into a 100-mL round-bottom flask, was placed a solution of(2R)-2-[[(2S)-2-[(2R)-2-[[(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoyl]oxy]-N-methylpropanamido]-4-fluoro-4-methylpentanoyl]oxy]-3-[4-(trifluoromethoxy)phenyl]propanoicacid ((TC10-18), 1.2 g, 1.73 mmol, 1.00 equiv) in dichloromethane (30mL),(1R)-1-[(2S)-1-[(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)-phenyl]pro-pan-2-yl]oxy-4-fluoro-4-methyl-1-oxopentan-2-yl](methyl)carbamoylethyl(2R)-4-methyl-2-(methylamino)-pentanoate HCl ((TA10-18A), 1.49 g, 2.07mmol, 1.20 equiv), DIEA (890 mg, 6.89 mmol, 4.00 equiv) and BOP-Cl (880mg, 3.45 mmol, 2.00 equiv). The resulting solution was stirred for 6 hat 25° C. and then concentrated under vacuum. The residue was purifiedby Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 silica gel; mobile phase, H₂O and CH₃CN (50% CH₃CN increasing to100% within 9 min); Detector, UV 220 nm. This resulted in 1.3 g (55%) of(R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethoxy)phenyl)propan-2-yl(S)-4-fluoro-2-((6S,9R, 12S,15R,18R,21R)-12-(2-fluoro-2-methylpropyl)-6,18-diisobutyl-N,2,2,5,9,11,17,21-octamethyl-4,7,10,13,16,19-hexaoxo-15-(4-(trifluoromethoxy)benzyl)-3,8,14,20-tetraoxa-5,11,17-triazadocosan-22-amido)-4-methylpentanoateas colorless oil. (ES, m/z): 1362 [M+H]⁺.

(6S,9R,12S,15R,18R,21R,24S,27R)-12,24-bis(2-fluoro-2-methylpropyl)-6,18-diisobutyl-2,2,5,9,11,17,21,23-octamethyl-4,7,10,13,16,19,22,25-octaoxo-15,27-bis(4-(trifluoromethoxy)benzyl)-3,8,14,20,26-pentaoxa-5,11,17,23-tetraazaoctacosan-28-oicacid (OC10-18A)

Into a 100-mL round-bottom flask, was placed a solution of(R)-1-(benzyloxy)-1-oxo-3-(4-(trifluoromethoxy)phenyl)propan-2-yl(S)-4-fluoro-2-((6S,9R, 12S, 15R,18R,21R)-12-(2-fluoro-2-methylpropyl)-6,18-diisobutyl-N,2,2,5,9,11,17,21-octamethyl-4,7,10,13,16,19-hexaoxo-15-(4-(trifluoromethoxy)benzyl)-3,8,14,20-tetraoxa-5,11,17-triazadocosan-22-amido)-4-methylpentanoate((OP10-18A), 1 g, 0.73 mmol, 1.00 equiv) in ethyl acetate (20 mL), andthe flask was evacuated and flushed three times with nitrogen. Palladiumon carbon (100 mg) was added and the flask was flushed with hydrogen.The resulting solution was stirred for 3 h at 25° C. and then the solidswere filtered out. The filtrate was concentrated under vacuum. Thisresulted in 660 mg (71%) of(6S,9R,12S,15R,18R,21R,24S,27R)-12,24-bis(2-fluoro-2-methylpropyl)-6,18-diisobutyl-2,2,5,9,11,17,21,23-octamethyl-4,7,10,13,16,19,22,25-octaoxo-15,27-bis(4-(trifluoromethoxy)benzyl)-3,8,14,20,26-pentaoxa-5,11,17,23-tetraazaoctacosan-28-oicacid as colorless oil. (ES, m/z): 1272 [M+H]⁺.

(3S,6R,9S,12R,15R,18R,21S,24R)-9,21-bis(2-fluoro-2-methylpropyl)-3,15-diisobutyl-6,8,14,18,20-pentamethyl-4,7,10,13,16,19,22-heptaoxo-12,24-bis(4-(trifluoromethoxy)benzyl)-5,11,17,23-tetraoxa-2,8,14,20-tetraazapentacosan-25-oicacid hydrochloride (OAC10-18A)

Into a 100-mL round-bottom flask, was placed a solution of (6S,9R,12S,15R,18R,21R,24S,27R)-12,24-bis(2-fluoro-2-methylpropyl)-6,18-diisobutyl-2,2,5,9,11,17,21,23-octamethyl-4,7,10,13,16,19,22,25-octaoxo-15,27-bis(4-(trifluoromethoxy)benzyl)-3,8,14,20,26-pentaoxa-5,11,17,23-tetraazaoctacosan-28-oicacid ((OC10-18A), 300 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (3mL), HCl (g)/Dioxane (20 mL, 4 N). The resulting solution was stirredfor 3 h at 0° C. The resulting mixture was concentrated under vacuum.This resulted in 270 mg (95%) of (3 S,6R,9S, 12R, 15R, 18R,21S,24R)-9,21-bis(2-fluoro-2-methylpropyl)-3,15-diisobutyl-6,8,14,18,20-pentamethyl-4,7,10,13,16,19,22-heptaoxo-12,24-bis(4-(trifluoromethoxy)benzyl)-5,11,17,23-tetraoxa-2,8,14,20-tetraazapentacosan-25-oicacid hydrochloride as colorless oil. (ES, m/z): 1172 [M+H-HCl]+.

(3S,6R,9S,12R,15R,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(10-18/2-4)

Into a 50-mL round-bottom flask, was placed a solution of (3 S,6R,9S,12R, 15R, 18R,21S,24R)-9,21-bis(2-fluoro-2-methylpropyl)-3,15-diisobutyl-6,8,14,18,20-pentamethyl-4,7,10,13,16,19,22-heptaoxo-12,24-bis(4-(trifluoromethoxy)benzyl)-5,11,17,23-tetraoxa-2,8,14,20-tetraazapentacosan-25-oicacid hydrochloride ((OAC10-18A), 300 mg, 0.25 mmol, 1.00 equiv) indichloromethane (15 mL), BOP-Cl (126.7 mg, 0.50 mmol, 2.00 equiv), DIEA(128.1 mg, 0.99 mmol, 4.00 equiv). The resulting solution was stirredfor 3 h at 25° C. The resulting mixture was concentrated under vacuum.The resulting solution was dissolved with 20 mL of CH₃CN. The solidswere filtered out. The filtrate was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, H₂O and CH₃CN (55% CH₃CN increasing to 95% within 9 min);Detector, UV 220 nm. This resulted in 53.1 mg (19%) of (3S,6R,9S,12R,15R,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octoneas a white solid. (ES, m/z): 1153.75 [M+H]+; ¹H NMR (CDCl₃, 300 MHz,ppm) δ 7.33-7.21 (m, 4H), 7.21-7.08 (m, 4H), 5.70-4.40 (m, 8H),3.30-2.70 (m, 16H), 2.30-1.10 (m, 28H), 1.00-0.70 (m, 12H); [a]=−14.6°,T=27.2° C., C=0.12 g/100 mL in MeOH.

Preparation Example 93: Preparation of Compound 10-18/1-15

Compound 10-18/1-15 was prepared according to schemes 45-47 shown belowstarting from dimer compounds DC60 and DA61land using reactionconditions and reagents similar to those shown above for Examples 90, 91and 92 to prepare the cyclization precursor OAC10-18. The peptidecoupling reactions shown are well known and would be clear to a personof skill in the art.

Experimental details for last step (3S,6S,9S,12S,15S,18S,21S,24S)-9,21-bis(2-fluoro-2-methylpropyl)-2,6,8,14,18,20-hexamethyl-3,15-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,5,11,17,23-pentaoxa-2,8,14,20-tetraazacyclopentacosan-4,7,10,13,16,19,22,25-octone(10-18/1-15)

Into a 50-mL round-bottom flask, was placed(3S,6S,9S,12S,15S,18S,21S,24S)-9,21-bis(2-fluoro-2-methylpropyl)-3,15-diisobutyl-6,8,14,18,20-pentamethyl-4,7,10,13,16,19,22-heptaoxo-12,24-bis(4-(trifluoromethoxy)benzyl)-5,11,17,23-tetraoxa-2,8,14,20-tetraazapentacosan-25-oicacid hydrochloride ((OAC10-18B), 300 mg (crude), 0.25 mmol, 1.00 equiv)and dichloromethane (30 mL). This was followed by the addition of BOP-Cl(130 mg, 0.50 mmol, 2.00 equiv), in portions at 0° C. To this was addedDIEA (99 mg, 0.75 mmol, 3.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 6 h at 20-30° C. and then the solidswere filtered out. The resulting mixture was concentrated under vacuumand the residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 45.1 mg of(3S,6S,9S,12S,15S,18S,21S,24S)-9,21-bis(2-fluoro-2-methylpropyl)-2,6,8,14,18,20-hexamethyl-3,15-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,5,11,17,23-pentaoxa-2,8,14,20-tetraazacyclopentacosan-4,7,10,13,16,19,22,25-octoneas a white solid. (ES, m/z): 1153.7 [M+H]+; ¹H NMR (CDCl₃, 300 MHz, ppm)δ 7.27-7.24 (m, 4H), 7.12-7.10 (m, 4H), 5.95-5.28 (m, 6H), 3.26-2.57 (m,12H), 2.51-2.25 (m, 8H), 1.83-1.25 (m, 26H), 0.97-0.84 (m, 12H);[a]=−88.5°, T=27.2° C., C=0.16 g/100 mL in MeOH.

Preparation Example 94: Preparation of Compound 10-18/2-3

Compound 10-18/2-3 was prepared according to schemes 48-50 shown belowstarting from dimer compounds DA62 and DC9 and using reaction conditionsand reagents similar to those shown above for Examples 90-92 to preparethe cyclization precursor OAC10-18C.

Experimental Details of Last Step(3S,6R,9S,12R,15R,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,106,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octone(10-18/2-3)

Into a 50-mL round-bottom flask, was placed (3 S,6R,9S,12R,15S,18R,21R,24R)-9,21-bis(2-fluoro-2-methylpropyl)-3,15-diisobutyl-6,8,14,18,20-pentamethyl-4,7,10,13,16,19,22-heptaoxo-12,24-bis(4-(trifluoromethoxy)benzyl)-5,11,17,23-tetraoxa-2,8,14,20-tetraazapentacosan-25-oicacid hydrochloride ((OAC10-18C), 600 mg, 0.50 mmol, 1.00 equiv),dichloromethane (10 mL), BOP-Cl (255 mg, 1.00 mmol, 2.00 equiv) and DIEA(258 mg, 2.00 mmol, 4.00 equiv). The resulting solution was stirred for3 h at 20° C. and then concentrated under vacuum. The resultingconcentrated solution was diluted with 5 mL of CH₃CN. The crude product(5 mL) was purified by Prep-HPLC with the following conditions(Prep-HPLC-007): Column, XBridge Prep C18 OBD Column, 19×220 mm, 5 um,10 nm; mobile phase, Water and CH₃CN (60.0% CH₃CN up to 79.0% in 6 min,hold 95.0% in 1 min, down to 60.0% in 1 min, hold 60.0% in 1 min);Detector, UV 220 nm. This resulted in 341 mg (59%) of(3S,6R,9S,12R,15R,18R,21S,24R)-3,15-bis(2-fluoro-2-methylpropyl)-4,6,10,16,18,22-hexamethyl-9,21-bis(2-methylpropyl)-12,24-bis([[4-(trifluoromethoxy)phenyl]methyl])-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octoneas a white solid. (ES, m/z): 1153.7 [M+H]+; ¹H NMR (CDCl₃, 300 MHz, ppm)δ 7.31-7.29 (m, 4H), 7.18-7.13 (m, 4H), 5.85-4.43 (m, 8H), 3.36-2.66 (m,16H), 2.34-1.94 (m, 4H), 1.68-1.21 (m, 22H), 1.10-0.67 (m, 14H).[a]=−13.3°, T=27.2° C., C=0.26 g/100 mL in MeOH.

In addition to the compounds described in the preparation examplesabove, the compounds in Table 121 below were prepared and characterizedas demonstrated by the mass spectra data provided for each compound. Asnoted above, the compounds are numbered according to the substitutionpattern of variables R^(a), R^(b), R¹, R², R³, R⁴, Cy¹ and Cy² informula (I) shown in Tables 7-44 and the stereochemical configurationdescribed in Tables 1 to 5 above. The compounds were also characterizedby the analytical techniques shown in examples XX-YY above.

Compound # m/z [M + H]⁺ 10-27/1-3 949 10-27/1-2 949 25-27/1-3 105725-27/1-1 1057  7-27/1-16 949 44-18/1-3 1185 10-18/1-16 1154 10-18/1-91154 10/18/1-12 1154 10-18/1-1 1154

Biological Activity Examples

METHOD A: Screening Method to Test Activity of Compounds AgainstMicrofilaria of Dirofilaria immitis.

Microfilaria of Dirofilaria immitis were added to the wells of amicrotitre plate containing buffer and the test compounds in DMSO. Anassessment was conducted at 72 hours to determine survival of themicrofilaria. Microfilaria exposed to DMSO alone served as controls.Compound #7-17/1-16, 10-18/1-3, 10-18/1-16 and 10-18/1-12 weredetermined to have EC₅₀ values of less than 10 μM. Compound #44-46/1-4(natural configuration), 7-27/1-2, 10-18/1-1 and exhibited mean EC₅₀values of less than 1 μM.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1.

or a veterinarily acceptable salt thereof, wherein: Cy¹ and Cy² areindependently aryl, carbocyclic, heteroaryl or heterocyclic optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, thioamido, amino, alkylamino, dialkylamino, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—,R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—,R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, wherein each cycloalkyl, heteroalkyl, aryl or heteroaryl isoptionally further substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—,—CN and —NO₂; R⁵ and R⁶ are independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, or the group —CH₂C(O)NHCH₂CF₃; or R⁵and R⁶ together with the atom(s) to which they are bonded form a C₃-C₆cyclic group; R′, R″, R″′ and R″″ are each independently hydrogen orC₁-C₃alkyl; R^(a) and R^(b) are independently hydrogen, C₁-C₃alkyl orC₁-C₃haloalkyl; and (a) R¹ is C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R², R³ and R⁴ are each independently C₁-C₈ alkyl; or(b) R² is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R¹, R³ and R⁴ are eachindependently C₁-C₈ alkyl; or (c) R³ is C₁-C₈ alkyl substituted by oneor more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹, R² and R⁴ are each independentlyC₁-C₈ alkyl; or (d) R⁴ is C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R¹, R² and R³ are each independently C₁-C₈ alkyl; or(e) R¹ and R² are each independently C₁-C₈ alkyl substituted by one ormore substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R³ and R⁴ are each independently C₁-C₈alkyl; or (f) R¹ and R³ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are each independently C₁-C₈alkyl; or (g) R¹ and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R³ are each independently C₁-C₈alkyl; or (h) R² and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are each independently C₁-C₈alkyl; or (i) R² and R³ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R⁴ are each independently C₁-C₈alkyl; or (j) R³ and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R² are each independently C₁-C₈alkyl; or (k) R¹, R² and R³ are each independently C₁-C₈ alkylsubstituted by one or more substituents selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R⁴ is C₁-C₈ alkyl; or (l) R², R³ and R⁴are each independently C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R¹ is C₁-C₈ alkyl; or (m) R¹, R³ and R⁴ are eachindependently C₁-C₈ alkyl substituted by one or more substituentsselected from the group consisting of aryl, heteroaryl, heterocyclyl,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R² isC₁-C₈ alkyl; or (n) R¹, R² and R⁴ are each independently C₁-C₈ alkylsubstituted by one or more substituents selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino andalkylamino, dialkylamino; and R³ is C₁-C₈ alkyl; or (o) R¹, R², R³ andR⁴ are each independently C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and wherein the carbon atoms bearing the groups —CH₂—Cy¹,—CH₂—Cy², R¹, R², R³, R⁴, R^(a) and R^(b) have the stereochemicalconfigurations in one of the entries presented in Tables 1 to 5 below:TABLE 1 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 (S) (R) (S)(S) (S) (S) (R) (R) 2 (R) (S) (S) (S) (S) (S) (R) (R) 3 (S) (S) (S) (S)(S) (S) (R) (R) 4 (S) (R) (S) (S) (S) (S) (S) (R) 5 (R) (S) (S) (S) (S)(S) (S) (R) 6 (S) (S) (S) (S) (S) (S) (S) (R) 7 (R) (R) (S) (S) (S) (S)(S) (R) 8 (S) (R) (S) (S) (S) (S) (R) (S) 9 (R) (S) (S) (S) (S) (S) (R)(S) 10 (S) (S) (S) (S) (S) (S) (R) (S) 11 (R) (R) (S) (S) (S) (S) (R)(S) 12 (S) (R) (S) (S) (S) (S) (S) (S) 13 (R) (S) (S) (S) (S) (S) (S)(S) 14 (S) (S) (S) (S) (S) (S) (S) (S) 15 (R) (R) (S) (S) (S) (S) (S)(S)

TABLE 2 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 (R) (R) (R)(S) (S) (S) (R) (R) 2 (R) (R) (S) (R) (S) (S) (R) (R) 3 (R) (R) (S) (S)(R) (S) (R) (R) 4 (R) (R) (S) (S) (S) (R) (R) (R) 5 (R) (R) (R) (S) (R)(S) (R) (R) 6 (R) (R) (S) (R) (S) (R) (R) (R) 7 (R) (R) (R) (R) (S) (S)(R) (R) 8 (R) (R) (S) (S) (R) (R) (R) (R) 9 (R) (R) (S) (R) (R) (S) (R)(R) 10 (R) (R) (R) (S) (S) (R) (R) (R) 11 (R) (R) (R) (R) (R) (S) (R)(R) 12 (R) (R) (S) (R) (R) (R) (R) (R) 13 (R) (R) (R) (S) (R) (R) (R)(R) 14 (R) (R) (R) (R) (S) (R) (R) (R) 15 (R) (R) (R) (R) (R) (R) (R)(R) 16 (R) (R) (R) (S) (S) (S) (S) (R) 17 (R) (R) (S) (R) (S) (S) (S)(R) 18 (R) (R) (S) (S) (R) (S) (S) (R) 19 (R) (R) (S) (S) (S) (R) (S)(R) 20 (R) (R) (R) (S) (R) (S) (S) (R) 21 (R) (R) (S) (R) (S) (R) (S)(R) 22 (R) (R) (R) (R) (S) (S) (S) (R) 23 (R) (R) (S) (R) (R) (S) (S)(R) 24 (R) (R) (S) (S) (R) (R) (S) (R) 25 (R) (R) (R) (S) (S) (R) (S)(R) 26 (R) (R) (R) (R) (R) (S) (S) (R) 27 (R) (R) (S) (R) (R) (R) (S)(R) 28 (R) (R) (R) (S) (R) (R) (S) (R) 29 (R) (R) (R) (R) (S) (R) (S)(R) 30 (R) (R) (R) (R) (R) (R) (S) (R) 31 (R) (R) (R) (S) (S) (S) (R)(S) 32 (R) (R) (S) (R) (S) (S) (R) (S) 33 (R) (R) (S) (S) (R) (S) (R)(S) 34 (R) (R) (S) (S) (S) (R) (R) (S) 35 (R) (R) (R) (S) (R) (S) (R)(S) 36 (R) (R) (S) (R) (S) (R) (R) (S) 37 (R) (R) (R) (R) (S) (S) (R)(S) 38 (R) (R) (S) (R) (R) (S) (R) (S) 39 (R) (R) (S) (S) (R) (R) (R)(S) 40 (R) (R) (R) (S) (S) (R) (R) (S) 41 (R) (R) (R) (R) (R) (S) (R)(S) 42 (R) (R) (S) (R) (R) (R) (R) (S) 43 (R) (R) (R) (S) (R) (R) (R)(S) 44 (R) (R) (R) (R) (S) (R) (R) (S) 45 (R) (R) (R) (R) (R) (R) (R)(S) 46 (R) (R) (R) (S) (S) (S) (S) (S) 47 (R) (R) (S) (R) (S) (S) (S)(S) 48 (R) (R) (S) (S) (R) (S) (S) (S) 49 (R) (R) (S) (S) (S) (R) (S)(S) 50 (R) (R) (R) (S) (R) (S) (S) (S) 51 (R) (R) (S) (R) (S) (R) (S)(S) 52 (R) (R) (R) (R) (S) (S) (S) (S) 53 (R) (R) (S) (R) (R) (S) (S)(S) 54 (R) (R) (S) (S) (R) (R) (S) (S) 55 (R) (R) (R) (S) (S) (R) (S)(S) 56 (R) (R) (R) (R) (R) (S) (S) (S) 57 (R) (R) (S) (R) (R) (R) (S)(S) 58 (R) (R) (R) (S) (R) (R) (S) (S) 59 (R) (R) (R) (R) (S) (R) (S)(S) 60 (R) (R) (R) (R) (R) (R) (S) (S)

TABLE 3 Entry —CH₂CY¹ —CH₂CY² R¹ R² R³ R⁴ R^(a) R^(b) 1 (S) (R) (R) (S)(S) (S) (R) (R) 2 (S) (R) (S) (R) (S) (S) (R) (R) 3 (S) (R) (S) (S) (R)(S) (R) (R) 4 (S) (R) (S) (S) (S) (R) (R) (R) 5 (S) (R) (R) (S) (R) (S)(R) (R) 6 (S) (R) (S) (R) (S) (R) (R) (R) 7 (S) (R) (R) (R) (S) (S) (R)(R) 8 (S) (R) (S) (R) (R) (S) (R) (R) 9 (S) (R) (S) (S) (R) (R) (R) (R)10 (S) (R) (R) (S) (S) (R) (R) (R) 11 (S) (R) (R) (R) (R) (S) (R) (R) 12(S) (R) (S) (R) (R) (R) (R) (R) 13 (S) (R) (R) (S) (R) (R) (R) (R) 14(S) (R) (R) (R) (S) (R) (R) (R) 15 (S) (R) (R) (R) (R) (R) (R) (R) 16(S) (R) (R) (S) (S) (S) (S) (R) 17 (S) (R) (S) (R) (S) (S) (S) (R) 18(S) (R) (S) (S) (R) (S) (S) (R) 19 (S) (R) (S) (S) (S) (R) (S) (R) 20(S) (R) (R) (S) (R) (S) (S) (R) 21 (S) (R) (S) (R) (S) (R) (S) (R) 22(S) (R) (R) (R) (S) (S) (S) (R) 23 (S) (R) (S) (R) (R) (S) (S) (R) 24(S) (R) (S) (S) (R) (R) (S) (R) 25 (S) (R) (R) (S) (S) (R) (S) (R) 26(S) (R) (R) (R) (R) (S) (S) (R) 27 (S) (R) (S) (R) (R) (R) (S) (R) 28(S) (R) (R) (S) (R) (R) (S) (R) 29 (S) (R) (R) (R) (S) (R) (S) (R) 30(S) (R) (R) (R) (R) (R) (S) (R) 31 (S) (R) (R) (S) (S) (S) (R) (S) 32(S) (R) (S) (R) (S) (S) (R) (S) 33 (S) (R) (S) (S) (R) (S) (R) (S) 34(S) (R) (S) (S) (S) (R) (R) (S) 35 (S) (R) (R) (S) (R) (S) (R) (S) 36(S) (R) (S) (R) (S) (R) (R) (S) 37 (S) (R) (R) (R) (S) (S) (R) (S) 38(S) (R) (S) (R) (R) (S) (R) (S) 39 (S) (R) (S) (S) (R) (R) (R) (S) 40(S) (R) (R) (S) (S) (R) (R) (S) 41 (S) (R) (R) (R) (R) (S) (R) (S) 42(S) (R) (S) (R) (R) (R) (R) (S) 43 (S) (R) (R) (S) (R) (R) (R) (S) 44(S) (R) (R) (R) (S) (R) (R) (S) 45 (S) (R) (R) (R) (R) (R) (R) (S) 46(S) (R) (R) (S) (S) (S) (S) (S) 47 (S) (R) (S) (R) (S) (S) (S) (S) 48(S) (R) (S) (S) (R) (S) (S) (S) 49 (S) (R) (S) (S) (S) (R) (S) (S) 50(S) (R) (R) (S) (R) (S) (S) (S) 51 (S) (R) (S) (R) (S) (R) (S) (S) 52(S) (R) (R) (R) (S) (S) (S) (S) 53 (S) (R) (S) (R) (R) (S) (S) (S) 54(S) (R) (S) (S) (R) (R) (S) (S) 55 (S) (R) (R) (S) (S) (R) (S) (S) 56(S) (R) (R) (R) (R) (S) (S) (S) 57 (S) (R) (S) (R) (R) (R) (S) (S) 58(S) (R) (R) (S) (R) (R) (S) (S) 59 (S) (R) (R) (R) (S) (R) (S) (S) 60(S) (R) (R) (R) (R) (R) (S) (S)

TABLE 4 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 (R) (S) (R)(S) (S) (S) (R) (R) 2 (R) (S) (S) (R) (S) (S) (R) (R) 3 (R) (S) (S) (S)(R) (S) (R) (R) 4 (R) (S) (S) (S) (S) (R) (R) (R) 5 (R) (S) (R) (S) (R)(S) (R) (R) 6 (R) (S) (S) (R) (S) (R) (R) (R) 7 (R) (S) (R) (R) (S) (S)(R) (R) 8 (R) (S) (S) (S) (R) (R) (R) (R) 9 (R) (S) (S) (R) (R) (S) (R)(R) 10 (R) (S) (R) (S) (S) (R) (R) (R) 11 (R) (S) (R) (R) (R) (S) (R)(R) 12 (R) (S) (S) (R) (R) (R) (R) (R) 13 (R) (S) (R) (S) (R) (R) (R)(R) 14 (R) (S) (R) (R) (S) (R) (R) (R) 15 (R) (S) (R) (R) (R) (R) (R)(R) 16 (R) (S) (R) (S) (S) (S) (S) (R) 17 (R) (S) (S) (R) (S) (S) (S)(R) 18 (R) (S) (S) (S) (R) (S) (S) (R) 19 (R) (S) (S) (S) (S) (R) (S)(R) 20 (R) (S) (R) (S) (R) (S) (S) (R) 21 (R) (S) (S) (R) (S) (R) (S)(R) 22 (R) (S) (R) (R) (S) (S) (S) (R) 23 (R) (S) (S) (R) (R) (S) (S)(R) 24 (R) (S) (S) (S) (R) (R) (S) (R) 25 (R) (S) (R) (S) (S) (R) (S)(R) 26 (R) (S) (R) (R) (R) (S) (S) (R) 27 (R) (S) (S) (R) (R) (R) (S)(R) 28 (R) (S) (R) (S) (R) (R) (S) (R) 29 (R) (S) (R) (R) (S) (R) (S)(R) 30 (R) (S) (R) (R) (R) (R) (S) (R) 31 (R) (S) (R) (S) (S) (S) (R)(S) 32 (R) (S) (S) (R) (S) (S) (R) (S) 33 (R) (S) (S) (S) (R) (S) (R)(S) 34 (R) (S) (S) (S) (S) (R) (R) (S) 35 (R) (S) (R) (S) (R) (S) (R)(S) 36 (R) (S) (S) (R) (S) (R) (R) (S) 37 (R) (S) (R) (R) (S) (S) (R)(S) 38 (R) (S) (S) (R) (R) (S) (R) (S) 39 (R) (S) (S) (S) (R) (R) (R)(S) 40 (R) (S) (R) (S) (S) (R) (R) (S) 41 (R) (S) (R) (R) (R) (S) (R)(S) 42 (R) (S) (S) (R) (R) (R) (R) (S) 43 (R) (S) (R) (S) (R) (R) (R)(S) 44 (R) (S) (R) (R) (S) (R) (R) (S) 45 (R) (S) (R) (R) (R) (R) (R)(S) 46 (R) (S) (R) (S) (S) (S) (S) (S) 47 (R) (S) (S) (R) (S) (S) (S)(S) 48 (R) (S) (S) (S) (R) (S) (S) (S) 49 (R) (S) (S) (S) (S) (R) (S)(S) 50 (R) (S) (R) (S) (R) (S) (S) (S) 51 (R) (S) (S) (R) (S) (R) (S)(S) 52 (R) (S) (R) (R) (S) (S) (S) (S) 53 (R) (S) (S) (R) (R) (S) (S)(S) 54 (R) (S) (S) (S) (R) (R) (S) (S) 55 (R) (S) (R) (S) (S) (R) (S)(S) 56 (R) (S) (R) (R) (R) (S) (S) (S) 57 (R) (S) (S) (R) (R) (R) (S)(S) 58 (R) (S) (R) (S) (R) (R) (S) (S) 59 (R) (S) (R) (R) (S) (R) (S)(S) 60 (R) (S) (R) (R) (R) (R) (S) (S)

TABLE 5 Entry —CH₂-Cy¹ —CH₂-Cy² R¹ R² R³ R⁴ R^(a) R^(b) 1 (S) (S) (R)(S) (S) (S) (R) (R) 2 (S) (S) (R) (R) (S) (S) (R) (R) 3 (S) (S) (S) (S)(R) (S) (R) (R) 4 (S) (S) (S) (S) (S) (R) (R) (R) 5 (S) (S) (R) (S) (R)(S) (R) (R) 6 (S) (S) (S) (R) (S) (R) (R) (R) 7 (S) (S) (R) (R) (S) (S)(R) (R) 8 (S) (S) (S) (S) (R) (R) (R) (R) 9 (S) (S) (S) (R) (R) (S) (R)(R) 10 (S) (S) (R) (S) (S) (R) (R) (R) 11 (S) (S) (R) (R) (R) (S) (R)(R) 12 (S) (S) (S) (R) (R) (R) (R) (R) 13 (S) (S) (R) (S) (R) (R) (R)(R) 14 (S) (S) (R) (R) (S) (R) (R) (R) 15 (S) (S) (R) (R) (R) (R) (R)(R) 16 (S) (S) (R) (S) (S) (S) (S) (R) 17 (S) (S) (S) (R) (S) (S) (S)(R) 18 (S) (S) (S) (S) (R) (S) (S) (R) 19 (S) (S) (S) (S) (S) (R) (S)(R) 20 (S) (S) (R) (S) (R) (S) (S) (R) 21 (S) (S) (S) (R) (S) (R) (S)(R) 22 (S) (S) (R) (R) (S) (S) (S) (R) 23 (S) (S) (S) (R) (R) (S) (S)(R) 24 (S) (S) (S) (S) (R) (R) (S) (R) 25 (S) (S) (R) (S) (S) (R) (S)(R) 26 (S) (S) (R) (R) (R) (S) (S) (R) 27 (S) (S) (S) (R) (R) (R) (S)(R) 28 (S) (S) (R) (S) (R) (R) (S) (R) 29 (S) (S) (R) (R) (S) (R) (S)(R) 30 (S) (S) (R) (R) (R) (R) (S) (R) 31 (S) (S) (R) (S) (S) (S) (R)(S) 32 (S) (S) (S) (R) (S) (S) (R) (S) 33 (S) (S) (S) (S) (R) (S) (R)(S) 34 (S) (S) (S) (S) (S) (R) (R) (S) 35 (S) (S) (R) (S) (R) (S) (R)(S) 36 (S) (S) (S) (R) (S) (R) (R) (S) 37 (S) (S) (R) (R) (S) (S) (R)(S) 38 (S) (S) (S) (R) (R) (S) (R) (S) 39 (S) (S) (S) (S) (R) (R) (R)(S) 40 (S) (S) (R) (S) (S) (R) (R) (S) 41 (S) (S) (R) (R) (R) (S) (R)(S) 42 (S) (S) (S) (R) (R) (R) (R) (S) 43 (S) (S) (R) (S) (R) (R) (R)(S) 44 (S) (S) (R) (R) (S) (R) (R) (S) 45 (S) (S) (R) (R) (R) (R) (R)(S) 46 (S) (S) (R) (S) (S) (S) (S) (S) 47 (S) (S) (S) (R) (S) (S) (S)(S) 48 (S) (S) (S) (S) (R) (S) (S) (S) 49 (S) (S) (S) (S) (S) (R) (S)(S) 50 (S) (S) (R) (S) (R) (S) (S) (S) 51 (S) (S) (S) (R) (S) (R) (S)(S) 52 (S) (S) (R) (R) (S) (S) (S) (S) 53 (S) (S) (S) (R) (R) (S) (S)(S) 54 (S) (S) (S) (S) (R) (R) (S) (S) 55 (S) (S) (R) (S) (S) (R) (S)(S) 56 (S) (S) (R) (R) (R) (S) (S) (S) 57 (S) (S) (S) (R) (R) (R) (S)(S) 58 (S) (S) (R) (S) (R) (R) (S) (S) 59 (S) (S) (R) (R) (S) (R) (S)(S) 60 (S) (S) (R) (R) (R) (R) (S) (S)


2. The anthelmintic cyclic depsipeptide of claim 1, wherein thestereochemical configuration of the carbon atoms bearing the groups—CH₂—Cy¹ and —CH₂—Cy² is the configuration 1, 2 or 3 shown in the tablebelow: Entry —CH₂-Cy¹ —CH₂-Cy² 1 (S) (R) 2 (R) (S) 3 (S) (S);

the stereochemical configuration of the carbon atoms bearing R¹, R², R³,R⁴ is the (S)-configuration; and the stereochemical configuration of thecarbon atoms bearing R^(a) and R^(b) is the (R)-configuration.
 3. Theanthelmintic cyclic depsipeptide of claim 1, wherein the stereochemicalconfiguration of carbon atoms bearing the groups —CH₂—Cy¹, —CH₂—Cy², R¹,R², R³, R⁴ is the (S)-configuration, and the stereochemicalconfiguration of the carbon atoms bearing R^(a) and R^(b) is the(R)-configuration.
 4. The anthelmintic cyclic depsipeptide of any one ofclaims 1 to 3, wherein (f) R¹ and R³ are each independently C₁-C₈ alkylsubstituted by one or more substituents selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R⁴ are each independently C₁-C₈alkyl; or (h) R² and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R³ are each independently C₁-C₈alkyl; or (e) R¹ and R² are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R³ and R⁴ are each independently C₁-C₈alkyl; or (g) R¹ and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R² and R³ are each independently C₁-C₈alkyl; or (i) R² and R³ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R⁴ are each independently C₁-C₈alkyl; or (j) R³ and R⁴ are each independently C₁-C₈ alkyl substitutedby one or more substituents selected from the group consisting of aryl,heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ and R² are each independently C₁-C₈alkyl.
 5. The anthelmintic cyclic depsipeptide of any one of claims 1 to3, wherein (a) R¹ is C₁-C₈ alkyl substituted by one or more substituentsselected from the group consisting of aryl, heteroaryl, heterocyclyl,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R², R³and R⁴ are each independently C₁-C₈ alkyl; or (b) R² is C₁-C₈ alkylsubstituted by one or more substituents selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹, R³ and R⁴ are each independentlyC₁-C₈ alkyl; or (c) R³ is C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R¹, R² and R⁴ are each independently C₁-C₈ alkyl; or(d) R⁴ is C₁-C₈ alkyl substituted by one or more substituents selectedfrom the group consisting of aryl, heteroaryl, heterocyclyl, halogen,hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino; and R¹, R² and R³ are eachindependently C₁-C₈ alkyl.
 6. The anthelmintic cyclic depsipeptide ofany one of claims 1 to 3, wherein (k) R¹, R² and R³ are eachindependently C₁-C₈ alkyl substituted by one or more substituentsselected from the group consisting of aryl, heteroaryl, heterocyclyl,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino, alkylamino and dialkylamino; and R⁴ isC₁-C₈ alkyl; or (l) R², R³ and R⁴ are each independently C₁-C₈ alkylsubstituted by one or more substituents selected from the groupconsisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino,alkylamino and dialkylamino; and R¹ is C₁-C₈ alkyl; or (m) R¹, R³ and R⁴are each independently C₁-C₈ alkyl substituted by one or moresubstituents selected from the group consisting of aryl, heteroaryl,heterocyclyl, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkoxyalkoxy, oxo, cyano, amino, alkylamino anddialkylamino; and R² is C₁-C₈ alkyl; or (n) R¹, R² and R⁴ are eachindependently C₁-C₈ alkyl substituted by one or more substituentsselected from the group consisting of aryl, heteroaryl, heterocyclyl,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkoxyalkoxy, oxo, cyano, amino and alkylamino, dialkylamino; and R³ isC₁-C₈ alkyl.
 7. The anthelmintic cyclic depsipeptide of any one ofclaims 1 to 3, wherein (o) R¹, R², R³ and R⁴ are each independentlyC₁-C₈ alkyl substituted by one or more substituents selected from thegroup consisting of aryl, heteroaryl, heterocyclyl, halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkoxyalkoxy, oxo,cyano, amino, alkylamino and dialkylamino.
 8. The anthelmintic cyclicdepsipeptide of any of claims 1 to 7, wherein at least one of R¹, R², R³and R⁴ is C₁-C₈ alkyl substituted by halogen.
 9. The anthelmintic cyclicdepsipeptide of claim 8, wherein one of R¹, R², R³ and R⁴ is C₁-C₈ alkylsubstituted by halogen.
 10. The anthelmintic cyclic depsipeptide ofclaim 8, wherein two of R¹, R², R³ and R⁴ is C₁-C₈ alkyl substituted byhalogen.
 11. The anthelmintic cyclic depsipeptide of claim 8, whereinthree of R¹, R², R³ and R⁴ is C₁-C₈ alkyl substituted by halogen. 12.The anthelmintic cyclic depsipeptide of claim 8, wherein each of R¹, R²,R³ and R⁴ are C₁-C₈ alkyl substituted by halogen.
 13. The anthelminticcyclic depsipeptide of claim 10, wherein R¹ and R³ are C₁-C₈ alkylsubstituted by halogen.
 14. The anthelmintic cyclic depsipeptide ofclaim 10, wherein R² and R⁴ are C₁-C₈ alkyl substituted by halogen. 15.The anthelmintic cyclic depsipeptide of any one of claims 8 to 14,wherein halogen is fluoro.
 16. The anthelmintic cyclic depsipeptide ofany one of claims 1 to 15, wherein R¹, R², R³ and R⁴ are independentlyG-1:

wherein R^(1A), R^(1B), R^(1C), R^(1D) and R^(1E) are independentlyhydrogen, halogen, cyano, hydroxy, amino, C₁₋₃alkylamino,C₁₋₃haloalkylamino, C₁₋₃dialkylamino, C₁₋₃dihaloalkylamino, C₁₋₃alkyl,C₁₋₃haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, C₁₋₃alkylthio orC₁₋₃haloalkylthio.
 17. The anthelmintic cyclic depsipeptide of claim 16,wherein: R^(1A), R^(1B), R^(1C) are independently hydrogen, methyl,trifluoromethyl or fluoro; and R^(1D) and R^(1E) are independentlyhydrogen, methyl or fluoro.
 18. The anthelmintic cyclic depsipeptide ofclaim 17, wherein at least one of R¹, R², R³ and R⁴ is G-1 whereinR^(1A) is fluoro; and R^(1D) and R^(1E) are hydrogen.
 19. Theanthelmintic cyclic depsipeptide of claim 17, wherein at least one ofR¹, R², R³ and R⁴ is G-1 wherein: R^(1A), R^(1B), R^(1C) areindependently methyl or fluoro; and R^(1D) and R^(1E) are independentlyhydrogen or fluoro.
 20. The anthelmintic cyclic depsipeptide of claim 1,wherein at least one of R¹, R², R³ and R⁴ are CH₂F, CHF₂ or CF₃.
 21. Theanthelmintic cyclic depsipeptide of any of the preceding claims, whereinCy¹ and Cy² are independently phenyl, a 5-membered or a 6-memberedheteroaryl optionally substituted with halogen, hydroxy, alkoxy,haloalkoxy, alkylthio, haloalkylthio, thioamido, amino, alkylamino,dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R₅R₆NC(O)NR⁵—,R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂, cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, wherein each cycloalkyl, heteroalkyl,aryl or heteroaryl is optionally further substituted with one or moresubstituents selected from the group consisting of halogen, hydroxy,alkoxy, haloalkoxy, alkylthio, haloalkylthio, thioamido, amino,alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—,R₅R₆NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.
 22. Theanthelmintic cyclic depsipeptide of claim 21, wherein Cy¹ and Cy² areindependently phenyl, a 5-membered or a six-membered heteroarylsubstituted with halogen, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R⁵R⁶NC(O)— and heterocyclyl.
 23. Theanthelmintic cyclic depsipeptide of claim 22, wherein Cy¹ and Cy² areindependently phenyl, a 5-membered or a six-membered heteroarylsubstituted with heterocyclyl, fluoro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio or cyano.
 24. The anthelminticcyclic depsipeptide of claim 23, wherein Cy¹ and Cy² are independentlyphenyl, a 5-membered heteroaryl or pyridinyl substituted withmorpholinyl or tetrahydropyranyl.
 25. The anthelmintic cyclicdepsipeptide of claim 22, wherein Cy¹ and Cy² are independently phenyl,thienyl, oxazolyl, isothiazolyl, 1,3-4-thiadazolyl, pyrazolyl, furyl,imidazolyl, pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortetrazinyl independently optionally substituted with R⁵R⁶NC(O)—, whereinR⁵ and R⁶ are independently hydrogen, —CH₂C(O)NHCH₂CF₃ or R⁵ and R⁶together with the nitrogen atom to which they are bonded together form aC₃-C₆ cyclic amine.
 26. The anthelmintic cyclic depsipeptide of claim 1,wherein Cy¹ and Cy² are independently R¹ to R⁸:

wherein Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸ and Y⁹ are each independently C,CH or N; and X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen,halogen, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio,thioamido, amino, alkylamino, dialkylamino, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, SF₅, R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—,R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—, R⁵C(O)O—, R⁵C(O)NR⁶—, —CN, —NO₂,cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl, wherein eachcycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl is optionallyfurther independently substituted with one or more substituents selectedfrom the group consisting of halogen, hydroxy, alkoxy, haloalkoxy,alkylthio, haloalkylthio, thioamido, amino, alkylamino, dialkylamino,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SF₅,R⁵S(O)—, R⁵S(O)₂—, R⁵C(O)—, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, R⁵OC(O)—,R⁵C(O)O—, R⁵C(O)NR⁶—, —CN and —NO₂.
 27. The anthelmintic cyclicdepsipeptide of claim 26, wherein X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ areindependently hydrogen, halogen, hydroxy, alkoxy, haloalkoxy, alkylthio,haloalkylthio, R⁵R⁶NC(O)—, R⁵R⁶NC(O)NR⁵—, thioamido, amino, alkylaminoor dialkylamino.
 28. The anthelmintic cyclic depsipeptide of claim 26,wherein X¹, X², X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl.
 29. Theanthelmintic cyclic depsipeptide of claim 26, wherein X¹, X², X³, X⁴,X⁵, X⁶ and X⁷ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, CF₃, —CH₂CF₃, —CHFCF₃ or CF₂CF₃.30. The anthelmintic cyclic depsipeptide of claim 26, wherein X¹, X²,X³, X⁴, X⁵, X⁶ and X⁷ are independently hydrogen, hydroxy, methoxy,trifluoromethoxy, —OCH₂CF₃, —OCHFCF₃, —OCF₂CF₃, methylthio,trifluoromethylthio, —SCH₂CF₃, —SCHFCF₃ or —SCF₂CF₃.
 31. An anthelminticveterinary composition comprising an effective amount of an anthelminticcyclic depsipeptide of any of the preceeding claims, or apharmaceutically or veterinarily acceptable salt thereof, in combinationwith a veterinarily acceptable carrier.
 32. An anthelmintic veterinarycomposition comprising an effective amount of an anthelmintic cyclicdepsipeptide of any one of claims 1 to 30, or a pharmaceutically orveterinarily acceptable salt thereof, in combination with a secondparasiticidal active agent and a veterinarily acceptable carrier.
 33. Amethod for the treatment or prevention of a parasitic infection orinfestation in an animal comprising administering to the animal aparasiticidally effective amount of the anthelmintic cyclic depsipeptideof any one of claims 1 to 30, or a pharmaceutically or veterinarilyacceptable salt thereof, to the animal.
 34. The method of claim 33,wherein the method prevents a parasitic infection by Dirofilariaimmitis.
 35. Use of the anthelmintic cyclic depsipeptide of any one ofclaims 1 to 30, or a pharmaceutically or veterinarily acceptable saltthereof, for use in the treatment or prevention of a parasitic infectionor a parasitic infestation in an animal.
 36. Use of the anthelminticcyclic depsipeptide of any one of claims 1 to 30, or a pharmaceuticallyor veterinarily acceptable salt thereof, in the manufacture of amedicament for the treatment or prevention of a parasitic infection or aparasitic infestation in or on an animal.